Dr. Jarosz is an Associate Professor of Chemical and Systems Biology and of Developmental Biology at Stanford University. He is also a fellow of ChEM-H and a member of the Stanford Cancer Institute, Stanford Neurosciences Institute, and Bio-X. Dan received his B.S. in Chemistry from the University of Washington, where he also minored in Physics as part of the Early Entrance Program. He then moved to MIT to obtain a PhD in Biochemistry, where his thesis work established the function of a low-fidelity DNA polymerase with roles in cancer and infectious disease, and identified means through which its activity is regulated in normal biology and disease states.

Following his graduation in 2007, Dan pursued postdoctoral training in genetics and cell biology as a Damon Runyon Cancer Research Foundation Fellow at the Whitehead Institute for Biomedical Research. Here his work centered on the molecular chaperone Hsp90 – the so called ‘cancer chaperone’ – and its relationship to the capacity of genetic variation to produce new phenotypes. He also pioneered high throughput screening methods to investigate the physiological consequences of prion-like protein aggregation.

In 2013, Dr. Jarosz joined the Stanford faculty where the long-term goal of his NIH- and NSF-funded research program is to understand how some biological systems can remain unaltered for long periods, whereas others that are genetically identical undergo rapid diversification. This paradox lies at the heart of how neurons can be killed by improper expression of a single aggregation-prone protein, how cancer cells can tolerate accumulating mutation burden, and how disease-associated mutations have devastating consequences in some individuals, but no effect in others. The Jarosz lab employs multidisciplinary approaches ranging from chemical biology to systems-level quantitative genetics and uses models as diverse as baker’s yeast and the African turquoise killifish. Dan has been named an NIH New Innovator and has received scholarships from the Searle, Glenn, Packard, Kimmel, and Vallee Foundations, but is proudest of the Louis Pasteur Prize from the Belgian Brewing Society.

In addition to his research activities Dan runs graduate admissions for the Chemical & Systems Biology Department and co-directs Foundations in Experimental Biology, the flagship course for incoming biosciences PhD students in the School of Medicine. He also serves on the Executive Committee of the School of Medicine Faculty Senate and as a mentor for the Vice Provost of Graduate Education’s Solidarity, Leadership, Inclusion, and Diversity (SoLID) Mentorship program. Outside of Stanford, Dan enjoys hiking, skiing, and just about any way of spending time with his wife, Mirna, and their three young children, Mark, Justin, and Phoebe.

Administrative Appointments

  • Guest Professor, D-BIOL/Institut für Biochemie, ETH-Zürich, Switzerland (2020 - 2020)

Honors & Awards

  • Chipperfield Lecture, MIT (2020)
  • Hogg Distinguished Lecture, MD Anderson Cancer Center (2018)
  • Faculty Scholar, Bert and Kuggie Vallee Foundation (2017)
  • Award for Research in Biological Mechanisms of Aging, Glenn Foundation (2016)
  • Director's New Innovator Award, NIH (2015)
  • Science and Engineering Fellow, David and Lucile Packard Foundation (2015)
  • Kimmel Scholar, Sidney Kimmel Foundation for Cancer Research (2015)
  • NSF-CAREER Award, National Science Foundation (2015)
  • Searle Scholar, Kinship Foundation/Chicago Community Trust (2014)
  • Pathway to Independence (K99/R00) Award, National Institutes of Health (2011)
  • Postdoctoral Fellowship, Damon Runyon Cancer Research Foundation (2008-2010)
  • Transition School/Early Entrance Program, University of Washington (1996-2001)

Professional Education

  • Postdoctoral, Whitehead Institute for Biomedical Research, Genetics and Cell Biology (2012)
  • Ph.D., MIT, Biological Chemistry (2007)
  • B.S., University of Washington, Chemistry and Biochemistry (2001)

Current Research and Scholarly Interests

Survival in changing environments requires the acquisition of new heritable traits. However, mechanisms that safeguard the fidelity of DNA replication often limit the source of such novelty to relatively modest changes in the genetic code. Thus, the acquisition of new forms and functions is thought to be driven by rare variants that occur at random, and are enriched during times of stress. We have begun to study an intriguing alternative hypothesis: that intrinsic links between protein folding and virtually every biological trait provide multiple avenues through which environmental stress can directly elicit heritable variation that drives evolution, disease, and development.

Our aim is to identify and characterize these mechanisms at the molecular level, integrating our findings to gain insight into the interplay among genetic variation, phenotypic diversity, and environmental fluctuations in complex cellular systems. Much of our work centers on the specific influence of molecular chaperones, proteins that help other proteins fold. Other projects focus on the induction of epigenetic variation that can be passed from one generation to another via self-perpetuating changes in protein conformation. Our work employs multidisciplinary approaches including biochemistry, genome-scale analyses, high-throughput screening methodologies, live cell imaging, microfluidics, and quantitative genetic techniques. Ultimately we seek to not only to understand mechanisms that link environmental stress to the acquisition of biological novelty, but also to identify means of manipulating them for therapeutic benefit and harnessing their power to engineer synthetic signaling networks.

2023-24 Courses

Stanford Advisees

All Publications

  • Tissue-specific landscape of protein aggregation and quality control in an aging vertebrate. Developmental cell Chen, Y. R., Harel, I., Singh, P. P., Ziv, I., Moses, E., Goshtchevsky, U., Machado, B. E., Brunet, A., Jarosz, D. F. 2024


    Protein aggregation is a hallmark of age-related neurodegeneration. Yet, aggregation during normal aging and in tissues other than the brain is poorly understood. Here, we leverage the African turquoise killifish to systematically profile protein aggregates in seven tissues of an aging vertebrate. Age-dependent aggregation is strikingly tissue specific and not simply driven by protein expression differences. Experimental interrogation in killifish and yeast, combined with machine learning, indicates that this specificity is linked to protein-autonomous biophysical features and tissue-selective alterations in protein quality control. Co-aggregation of protein quality control machinery during aging may further reduce proteostasis capacity, exacerbating aggregate burden. A segmental progeria model with accelerated aging in specific tissues exhibits selectively increased aggregation in these same tissues. Intriguingly, many age-related protein aggregates arise in wild-type proteins that, when mutated, drive human diseases. Our data chart a comprehensive landscape of protein aggregation during vertebrate aging and identify strong, tissue-specific associations with dysfunction and disease.

    View details for DOI 10.1016/j.devcel.2024.04.014

    View details for PubMedID 38810654

  • Identification of protein aggregates in the aging vertebrate brain with prion-like and phase-separation properties. Cell reports Harel, I., Chen, Y. R., Ziv, I., Singh, P. P., Heinzer, D., Navarro Negredo, P., Goshtchevsky, U., Wang, W., Astre, G., Moses, E., McKay, A., Machado, B. E., Hebestreit, K., Yin, S., Sánchez Alvarado, A., Jarosz, D. F., Brunet, A. 2024: 112787


    Protein aggregation, which can sometimes spread in a prion-like manner, is a hallmark of neurodegenerative diseases. However, whether prion-like aggregates form during normal brain aging remains unknown. Here, we use quantitative proteomics in the African turquoise killifish to identify protein aggregates that accumulate in old vertebrate brains. These aggregates are enriched for prion-like RNA-binding proteins, notably the ATP-dependent RNA helicase DDX5. We validate that DDX5 forms aggregate-like puncta in the brains of old killifish and mice. Interestingly, DDX5's prion-like domain allows these aggregates to propagate across many generations in yeast. In vitro, DDX5 phase separates into condensates. Mutations that abolish DDX5 prion propagation also impair the protein's ability to phase separate. DDX5 condensates exhibit enhanced enzymatic activity, but they can mature into inactive, solid aggregates. Our findings suggest that protein aggregates with prion-like properties form during normal brain aging, which could have implications for the age-dependency of cognitive decline.

    View details for DOI 10.1016/j.celrep.2023.112787

    View details for PubMedID 38810650

  • In vivo protein turnover rates in varying oxygen tensions nominate MYBBP1A as a mediator of the hyperoxia response. Science advances Chen, X., Haribowo, A. G., Baik, A. H., Fossati, A., Stevenson, E., Chen, Y. R., Reyes, N. S., Peng, T., Matthay, M. A., Traglia, M., Pico, A. R., Jarosz, D. F., Buchwalter, A., Ghaemmaghami, S., Swaney, D. L., Jain, I. H. 2023; 9 (49): eadj4884


    Oxygen deprivation and excess are both toxic. Thus, the body's ability to adapt to varying oxygen tensions is critical for survival. While the hypoxia transcriptional response has been well studied, the post-translational effects of oxygen have been underexplored. In this study, we systematically investigate protein turnover rates in mouse heart, lung, and brain under different inhaled oxygen tensions. We find that the lung proteome is the most responsive to varying oxygen tensions. In particular, several extracellular matrix (ECM) proteins are stabilized in the lung under both hypoxia and hyperoxia. Furthermore, we show that complex 1 of the electron transport chain is destabilized in hyperoxia, in accordance with the exacerbation of associated disease models by hyperoxia and rescue by hypoxia. Moreover, we nominate MYBBP1A as a hyperoxia transcriptional regulator, particularly in the context of rRNA homeostasis. Overall, our study highlights the importance of varying oxygen tensions on protein turnover rates and identifies tissue-specific mediators of oxygen-dependent responses.

    View details for DOI 10.1126/sciadv.adj4884

    View details for PubMedID 38064566

  • Hsp90 shapes adaptation by controlling the fitness consequences of regulatory variation. bioRxiv : the preprint server for biology Jakobson, C. M., Aguilar-Rodríguez, J., Jarosz, D. F. 2023


    The essential stress-responsive chaperone Hsp90 impacts development and adaptation from microbes to humans. Yet despite evidence of its role in evolution, pathogenesis, and oncogenic transformation, the molecular mechanisms by which Hsp90 alters the consequences of mutations remain vigorously debated. Here we exploit the power of nucleotide-resolution genetic mapping in Saccharomyces cerevisiae to uncover more than 1,000 natural variant-to-phenotype associations governed by this molecular chaperone. Strikingly, Hsp90 more frequently modified the phenotypic effects of cis-regulatory variation than variants that altered protein sequence. Moreover, these interactions made the largest contribution to Hsp90-dependent heredity. Nearly all interacting variants-both regulatory and protein-coding-fell within clients of Hsp90 or targets of its direct binding partners. Hsp90 activity affected mutations in evolutionarily young genes, segmental deletions, and heterozygotes, highlighting its influence on variation central to evolutionary novelty. Reconciling the diverse epistatic effects of this chaperone, synthetic transcriptional regulation and reconstructions of natural alleles by genome editing revealed a central role for Hsp90 in regulating the fundamental relationship between activity and phenotype. Our findings establish that non-coding variation is a core driver of Hsp90's influence on heredity, offering a mechanistic explanation for the chaperone's strong effects on evolution and development across species.

    View details for DOI 10.1101/2023.10.30.564848

    View details for PubMedID 37961536

    View details for PubMedCentralID PMC10634948

  • Defining the condensate landscape of fusion oncoproteins. Nature communications Tripathi, S., Shirnekhi, H. K., Gorman, S. D., Chandra, B., Baggett, D. W., Park, C. G., Somjee, R., Lang, B., Hosseini, S. M., Pioso, B. J., Li, Y., Iacobucci, I., Gao, Q., Edmonson, M. N., Rice, S. V., Zhou, X., Bollinger, J., Mitrea, D. M., White, M. R., McGrail, D. J., Jarosz, D. F., Yi, S. S., Babu, M. M., Mullighan, C. G., Zhang, J., Sahni, N., Kriwacki, R. W. 2023; 14 (1): 6008


    Fusion oncoproteins (FOs) arise from chromosomal translocations in ~17% of cancers and are often oncogenic drivers. Although some FOs can promote oncogenesis by undergoing liquid-liquid phase separation (LLPS) to form aberrant biomolecular condensates, the generality of this phenomenon is unknown. We explored this question by testing 166 FOs in HeLa cells and found that 58% formed condensates. The condensate-forming FOs displayed physicochemical features distinct from those of condensate-negative FOs and segregated into distinct feature-based groups that aligned with their sub-cellular localization and biological function. Using Machine Learning, we developed a predictor of FO condensation behavior, and discovered that 67% of ~3000 additional FOs likely form condensates, with 35% of those predicted to function by altering gene expression. 47% of the predicted condensate-negative FOs were associated with cell signaling functions, suggesting a functional dichotomy between condensate-positive and -negative FOs. Our Datasets and reagents are rich resources to interrogate FO condensation in the future.

    View details for DOI 10.1038/s41467-023-41655-2

    View details for PubMedID 37770423

    View details for PubMedCentralID 5916809

  • Biomolecular Condensation: A New Phase in Cancer Research. Cancer discovery Chakravarty, A. K., McGrail, D. J., Lozanoski, T. M., Dunn, B. S., Shih, D. J., Cirillo, K. M., Cetinkaya, S. H., Zheng, W. J., Mills, G. B., Yi, S. S., Jarosz, D. F., Sahni, N. 2022: OF1-OF13


    Multicellularity was a watershed development in evolution. However, it also meant that individual cells could escape regulatory mechanisms that restrict proliferation at a severe cost to the organism: cancer. From the standpoint of cellular organization, evolutionary complexity scales to organize different molecules within the intracellular milieu. The recent realization that many biomolecules can "phase-separate" into membraneless organelles, reorganizing cellular biochemistry in space and time, has led to an explosion of research activity in this area. In this review, we explore mechanistic connections between phase separation and cancer-associated processes and emerging examples of how these become deranged in malignancy.SIGNIFICANCE: One of the fundamental functions of phase separation is to rapidly and dynamically respond to environmental perturbations. Importantly, these changes often lead to alterations in cancer-relevant pathways and processes. This review covers recent advances in the field, including emerging principles and mechanisms of phase separation in cancer.

    View details for DOI 10.1158/2159-8290.CD-21-1605

    View details for PubMedID 35852417

  • A colloidal polymer model for the condensnation of intrinsically disordered proteins Yang, T., Jarosz, D., Zia, R. N. CELL PRESS. 2022: 199A
  • Massive QTL analysis identifies pleiotropic genetic determinants for stress resistance, aroma formation, and ethanol, glycerol and isobutanol production in Saccharomyces cerevisiae. Biotechnology for biofuels Ho, P., Piampongsant, S., Gallone, B., Del Cortona, A., Peeters, P., Reijbroek, F., Verbaet, J., Herrera, B., Cortebeeck, J., Nolmans, R., Saels, V., Steensels, J., Jarosz, D. F., Verstrepen, K. J. 2021; 14 (1): 211


    BACKGROUND: The brewer's yeast Saccharomyces cerevisiae is exploited in several industrial processes, ranging from food and beverage fermentation to the production of biofuels, pharmaceuticals and complex chemicals. The large genetic and phenotypic diversity within this species offers a formidable natural resource to obtain superior strains, hybrids, and variants. However, most industrially relevant traits in S. cerevisiae strains are controlled by multiple genetic loci. Over the past years, several studies have identified some of these QTLs. However, because these studies only focus on a limited set of traits and often use different techniques and starting strains, a global view of industrially relevant QTLs is still missing.RESULTS: Here, we combined the power of 1125 fully sequenced inbred segregants with high-throughput phenotyping methods to identify as many as 678 QTLs across 18 different traits relevant to industrial fermentation processes, including production of ethanol, glycerol, isobutanol, acetic acid, sulfur dioxide, flavor-active esters, as well as resistance to ethanol, acetic acid, sulfite and high osmolarity. We identified and confirmed several variants that are associated with multiple different traits, indicating that many QTLs are pleiotropic. Moreover, we show that both rare and common variants, as well as variants located in coding and non-coding regions all contribute to the phenotypic variation.CONCLUSIONS: Our findings represent an important step in our understanding of the genetic underpinnings of industrially relevant yeast traits and open new routes to study complex genetics and genetic interactions as well as to engineer novel, superior industrial yeasts. Moreover, the major role of rare variants suggests that there is a plethora of different combinations of mutations that can be explored in genome editing.

    View details for DOI 10.1186/s13068-021-02059-w

    View details for PubMedID 34727964

  • Metabolites control stress granule disassembly. Nature cell biology Jakobson, C. M., Jarosz, D. F. 2021

    View details for DOI 10.1038/s41556-021-00768-w

    View details for PubMedID 34616025

  • Protein aggregation and the evolution of stress resistance in clinical yeast. Philosophical transactions of the Royal Society of London. Series B, Biological sciences Chen, Y. R., Ziv, I., Swaminathan, K., Elias, J. E., Jarosz, D. F. 2021; 376 (1826): 20200127


    Protein aggregation, particularly in its prion-like form, has long been thought to be detrimental. However, recent studies have identified multiple instances where protein aggregation is important for normal physiological functions. Combining mass spectrometry and cell biological approaches, we developed a strategy for the identification of protein aggregates in cell lysates. We used this approach to characterize prion-based traits in pathogenic strains of the yeast Saccharomyces cerevisiae isolated from immunocompromised human patients. The proteins that we found, including the metabolic enzyme Cdc19, the translation elongation factor Yef3 and the fibrillarin homologue Nop1, are known to assemble under certain physiological conditions. Yet, such assemblies have not been reported to be stable or heritable. Our data suggest that some proteins which aggregate in response to stress have the capacity to acquire diverse assembled states, certain ones of which can be propagated across generations in a form of protein-based epigenetics. This article is part of the theme issue 'How does epigenetics influence the course of evolution?'

    View details for DOI 10.1098/rstb.2020.0127

    View details for PubMedID 33866806

  • Protein self-assembly: A new frontier in cell signaling. Current opinion in cell biology Saad, S., Jarosz, D. F. 2021; 69: 62–69


    Long viewed as paradigm-shifting, but rare, prions have recently been discovered in all domains of life. Protein sequences that can drive this form of self-assembly are strikingly common in eukaryotic proteomes, where they are enriched in proteins involved in information flow and signal transduction. Although prions were thought to be a consequence of random errors in protein folding, recent studies suggest that prion formation can be a controlled process initiated by defined cellular signals. Many are present in normal biological contexts, yet are invisible to most technologies used to interrogate the proteome. Here, we review mechanisms by which protein self-assembly can create a stable record of past stimuli, altering adaptive responses, and how prion behavior is controlled by signaling processes. We touch on the diverse implications that this has for normal biological function and regulation, ranging from drug resistance in fungi to the innate immune response in humans. Finally, we discuss the potential for prion domains in transcription factors and RNA-binding proteins to orchestrate heritable gene expression changes in response to transient signals, such as during development.

    View details for DOI 10.1016/

    View details for PubMedID 33493989

  • The hunt for ancient prions: Archaeal prion-like domains form amyloid-based epigenetic elements. Molecular biology and evolution Zajkowski, T. n., Lee, M. D., Mondal, S. S., Carbajal, A. n., Dec, R. n., Brennock, P. D., Piast, R. W., Snyder, J. E., Bense, N. B., Dzwolak, W. n., Jarosz, D. F., Rothschild, L. J. 2021


    Prions, proteins that can convert between structurally and functionally distinct states and serve as non-Mendelian mechanisms of inheritance, were initially discovered and only known in eukaryotes, and consequently considered to likely be a relatively late evolutionary acquisition. However, the recent discovery of prions in bacteria and viruses has intimated a potentially more ancient evolutionary origin. Here we provide evidence that prion-forming domains exist in the domain archaea, the last domain of life left unexplored with regard to prions. We searched for archaeal candidate prion-forming protein sequences computationally, described their taxonomic distribution and phylogeny, and analyzed their associated functional annotations. Using biophysical in vitro assays, cell-based and microscopic approaches, and dye-binding analyses, we tested select candidate prion-forming domains for prionogenic characteristics. Out of the 16 tested, 8 formed amyloids, and 6 acted as protein-based elements of information transfer driving non-Mendelian patterns of inheritance. We also identified short peptides from our archaeal prion candidates that can form amyloid fibrils independently. Lastly, candidates that tested positively in our assays had significantly higher tyrosine and phenylalanine content than candidates that tested negatively, an observation that may help future archaeal prion predictions. Taken together, our discovery of functional prion-forming domains in archaea provides evidence that multiple archaeal proteins are capable of acting as prions-thus expanding our knowledge of this epigenetic phenomenon to the third and final domain of life and bolstering the possibility that they were present at the time of the last universal common ancestor (LUCA).

    View details for DOI 10.1093/molbev/msab010

    View details for PubMedID 33480998

  • A prion accelerates proliferation at the expense of lifespan. eLife Garcia, D. M., Campbell, E. A., Jakobson, C. M., Tsuchiya, M., Shaw, E. A., DiNardo, A. L., Kaeberlein, M., Jarosz, D. F. 2021; 10


    In fluctuating environments, switching between different growth strategies, such as those affecting cell size and proliferation, can be advantageous to an organism. Trade-offs arise, however. Mechanisms that aberrantly increase cell size or proliferation-such as mutations or chemicals that interfere with growth regulatory pathways-can also shorten lifespan. Here we report a natural example of how the interplay between growth and lifespan can be epigenetically controlled. We find that a highly conserved RNA-modifying enzyme, the pseudouridine synthase Pus4/TruB, can act as a prion, endowing yeast with greater proliferation rates at the cost of a shortened lifespan. Cells harboring the prion grow larger and exhibit altered protein synthesis. This epigenetic state, [BIG+] (better in growth), allows cells to heritably yet reversibly alter their translational program, leading to the differential synthesis of dozens of proteins, including many that regulate proliferation and aging. Our data reveal a new role for prion-based control of an RNA-modifying enzyme in driving heritable epigenetic states that transform cell growth and survival.

    View details for DOI 10.7554/eLife.60917

    View details for PubMedID 34545808

  • A Prion Epigenetic Switch Establishes an Active Chromatin State. Cell Harvey, Z. H., Chakravarty, A. K., Futia, R. A., Jarosz, D. F. 2020


    Covalent modifications to histones are essential for development, establishing distinct and functional chromatin domains from a common genetic sequence. Whereas repressed chromatin is robustly inherited, no mechanism that facilitates inheritance of an activated domain has been described. Here, we report that the Set3C histone deacetylase scaffold Snt1 can act as a prion that drives the emergence and transgenerational inheritance of an activated chromatin state. This prion, which we term [ESI+] for expressed sub-telomeric information, is triggered by transient Snt1 phosphorylation upon cell cycle arrest. Once engaged, the prion reshapes the activity of Snt1 and the Set3C complex, recruiting RNA pol II and interfering with Rap1 binding to activate genes in otherwise repressed sub-telomeric domains. This transcriptional state confers broad resistance to environmental stress, including antifungal drugs. Altogether, our results establish a robust means by which a prion can facilitate inheritance of an activated chromatin state to provide adaptive benefit.

    View details for DOI 10.1016/j.cell.2020.02.014

    View details for PubMedID 32109413

  • What Has a Century of Quantitative Genetics Taught Us About Nature's Genetic Toolkit? Annual review of genetics Jakobson, C. M., Jarosz, D. F. 2020


    The complexity of heredity has been appreciated for decades: Many traits are controlled not by a single genetic locus but instead by polymorphisms throughout the genome. The importance of complex traits in biology and medicine has motivated diverse approaches to understanding their detailed genetic bases. Here, we focus on recent systematic studies, many in budding yeast, which have revealed that large numbers of all kinds of molecular variation, from noncoding to synonymous variants, can make significant contributions to phenotype. Variants can affect different traits in opposing directions, and their contributions can be modified by both the environment and the epigenetic state of the cell. The integration of prospective (synthesizing and analyzing variants) and retrospective (examining standing variation) approaches promises to reveal how natural selection shapes quantitative traits. Only by comprehensively understanding nature's genetic tool kit can we predict how phenotypes arise from the complex ensembles of genetic variants in living organisms. Expected final online publication date for the Annual Review of Genetics, Volume 54 is November 23, 2020. Please see for revised estimates.

    View details for DOI 10.1146/annurev-genet-021920-102037

    View details for PubMedID 32897739

  • Both ROSy and Grim: The Landscape of Protein Redox during Aging. Cell metabolism Chen, Y. R., Jarosz, D. F. 2020; 31 (4): 662–63


    Covalent cysteine modification by reactive oxygen species (ROS) has been implicated in regulating diverse biological processes, yet global understanding of this modification has remained fragmentary. Developing new approaches for detecting cysteine modification, Xiao et al. (2020) recently charted a comprehensive map of cysteine oxidation across tissues and life stages.

    View details for DOI 10.1016/j.cmet.2020.03.016

    View details for PubMedID 32268111

  • Phase separation: from phenomenon to function. Molecular biology of the cell Woodruff, J. n., Jarosz, D. n. 2020; 31 (6): 405

    View details for DOI 10.1091/mbc.E20-01-0039

    View details for PubMedID 32163352

  • Widespread Prion-Based Control of Growth and Differentiation Strategies in Saccharomyces cerevisiae. Molecular cell Itakura, A. K., Chakravarty, A. K., Jakobson, C. M., Jarosz, D. F. 2019


    Theory and experiments suggest that organisms would benefit from pre-adaptation to future stressors based on reproducible environmental fluctuations experienced by their ancestors, but the mechanisms driving pre-adaptation remain enigmatic. We report that the [SMAUG+] prion allows yeast to anticipate nutrient repletion after periods of starvation, providing a strong selective advantage. By transforming the landscape of post-transcriptional gene expression, [SMAUG+] regulates the decision between two broad growth and survival strategies: mitotic proliferation or meiotic differentiation into a stress-resistant state. [SMAUG+] is common in laboratory yeast strains, where standard propagation practice produces regular cycles of nutrient scarcity followed by repletion. Distinct [SMAUG+] variants are also widespread in wild yeast isolates from multiple niches, establishing that prion polymorphs can be utilized in natural populations. Our data provide a striking example of how protein-based epigenetic switches, hidden in plain sight, can establish a transgenerational memory that integrates adaptive prediction into developmental decisions.

    View details for DOI 10.1016/j.molcel.2019.10.027

    View details for PubMedID 31757756

  • A Non-amyloid Prion Particle that Activates a Heritable Gene Expression Program. Molecular cell Chakravarty, A. K., Smejkal, T., Itakura, A. K., Garcia, D. M., Jarosz, D. F. 2019


    Spatiotemporal gene regulation is often driven by RNA-binding proteins that harbor long intrinsically disordered regions in addition to folded RNA-binding domains. We report that the disordered region of theevolutionarily ancient developmental regulator Vts1/Smaug drives self-assembly into gel-like condensates. These proteinaceous particles are not composed of amyloid, yet they are infectious, allowing them to act as a protein-based epigenetic element: a prion [SMAUG+]. In contrast to many amyloid prions, condensation of Vts1 enhances its function in mRNA decay, and its self-assembly properties are conserved over large evolutionary distances. Yeast cells harboring [SMAUG+] downregulate a coherent network of mRNAs and exhibit improved growth under nutrient limitation. Vts1 condensates formed from purified protein can transform naive cells to acquire [SMAUG+]. Our data establish that non-amyloid self-assembly of RNA-binding proteins can drive a form of epigenetics beyond the chromosome, instilling adaptive gene expression programs that are heritable over long biological timescales.

    View details for DOI 10.1016/j.molcel.2019.10.028

    View details for PubMedID 31757755

  • Molecular Origins of Complex Heritability in Natural Genotype-to-Phenotype Relationships CELL SYSTEMS Jakobson, C. M., Jarosz, D. F. 2019; 8 (5): 363-+
  • Remembering the past: a new form of protein-based inheritance Jarosz, D. F. TAYLOR & FRANCIS INC. 2019: 10
  • Molecular Origins of Complex Heritability in Natural Genotype-to-Phenotype Relationships. Cell systems Jakobson, C. M., Jarosz, D. F. 2019


    The statistical complexity of heredity has long been evident, but its molecular origins remain elusive. Toinvestigate, we charted 90 comprehensive genotype-to-phenotype maps in a large population of wild diploid yeast. In contrast to long-standing assumptions, all types of genetic variation contributed similarly to phenotype. Causal synonymous and regulatory variants exhibited distinct molecular signatures, as did nonlinearities in heterozygote fitness that likely contribute to hybrid vigor. Highly pleiotropic variants altered disordered sequences within signaling hubs, and their effects correlated across environments-even when antagonistic-suggesting that large fitness gains bring concomitant costs. Naturalgenetic networks defined by the causal loci differed from those determined by precise gene deletionsor protein-protein interactions. Finally, we found that traits that would appear omnigenic in less powered studies do in fact have finite genetic determinants.Integrating these molecular principles will be crucial as genome reading and writing become routine in research, industry, and medicine.

    View details for PubMedID 31054809

  • It's not magic-Hsp90 and its effects on genetic and epigenetic variation SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY Zabinsky, R. A., Mason, G., Queitsch, C., Jarosz, D. F. 2019; 88: 21–35
  • Molecular drivers and epigenetic modifiers of complex heritability revealed by a natural genotype-to-phenotype map Jakobson, C., Aguilar-Rodriguez, J., Jarosz, D. AMER CHEMICAL SOC. 2019
  • Pervasive function and evidence for selection across standing genetic variation in S. cerevisiae. Nature communications Jakobson, C. M., She, R., Jarosz, D. F. 2019; 10 (1): 1222


    Quantitative genetics aims to map genotype to phenotype, often with the goal of understanding how organisms evolved. However, it remains unclear whether the genetic variants identified are exemplary of evolution. Here we analyzed progeny of two wild Saccharomyces cerevisiae isolates to identify 195 loci underlying complex metabolic traits, resolving 107 to single polymorphisms with diverse molecular mechanisms. More than 20% of causal variants exhibited patterns of emergence inconsistent with neutrality. Moreover, contrary to drift-centric expectation, variation in diverse wild yeast isolates broadly exhibited this property: over 30% of shared natural variants exhibited phylogenetic signatures suggesting that they are not neutral. This pattern is likely attributable to both homoplasy and balancing selection on ancestral polymorphism. Variants that emerged repeatedly were more likely to have done so in isolates from the same ecological niche. Our results underscore the power of super-resolution mapping of ecologically relevant traits in understanding adaptation and evolution.

    View details for PubMedID 30874558

  • More than Just a Phase: Prions at the Crossroads of Epigenetic Inheritance and Evolutionary Change JOURNAL OF MOLECULAR BIOLOGY Chakravarty, A. K., Jarosz, D. F. 2018; 430 (23): 4607–18
  • Mutations, protein homeostasis, and epigenetic control of genome integrity. DNA repair Xie, J. L., Jarosz, D. F. 2018


    From bacteria to humans, ancient stress responses enable organisms to contend with damage to both the genome and the proteome. These pathways have long been viewed as fundamentally separate responses. Yet recent discoveries from multiple fields have revealed surprising links between the two. Many DNA-damaging agents also target proteins, and mutagenesis induced by DNA damage produces variant proteins that are prone to misfolding, degradation, and aggregation. Likewise, recent studies have observed pervasive engagement of a p53-mediated response, and other factors linked to maintenance of genomic integrity, in response to misfolded protein stress. Perhaps most remarkably, protein aggregation and self-assembly has now been observed in multiple proteins that regulate the DNA damage response. The importance of these connections is highlighted by disease models of both cancer and neurodegeneration, in which compromised DNA repair machinery leads to profound defects in protein quality control, and vice versa.

    View details for PubMedID 30181040

  • More than Just a Phase: Prions at the Crossroads of Epigenetic Inheritance and Evolutionary Change. Journal of molecular biology Chakravarty, A. K., Jarosz, D. F. 2018


    A central tenet of molecular biology is that heritable information is stored in nucleic acids. But this paradigm has been overturned by a group of proteins called 'prions'. Prion proteins, many of which are intrinsically disordered, can adopt multiple conformations, at least one of which has the capacity to self-template. This unusual folding landscape drives a form of extreme epigenetic inheritance that can be stable through both mitotic and meiotic cell divisions. Although the first prion discovered - mammalian PrP - is the causative agent of debilitating neuropathies, many additional prions have now been identified that are not obviously detrimental and can even be adaptive. Intrinsically disordered regions, which endow proteins with the bulk property of 'phase-separation,' can also be drivers of prion formation. Indeed, many protein domains that promote phase separation have been described as prion-like. In this review, we describe how prions lie at the crossroads of phase-separation, epigenetic inheritance and evolutionary adaptation.

    View details for PubMedID 30031007

  • It's not magic - Hsp90 and its effects on genetic and epigenetic variation. Seminars in cell & developmental biology Zabinsky, R. A., Mason, G. A., Queitsch, C., Jarosz, D. F. 2018


    Canalization, or phenotypic robustness in the face of environmental and genetic perturbation, is an emergent property of living systems. Although this phenomenon has long been recognized, its molecular underpinnings have remained enigmatic until recently. Here, we review the contributions of the molecular chaperone Hsp90, a protein that facilitates the folding of many key regulators of growth and development, to canalization of phenotype - and de-canalization in times of stress - drawing on studies in eukaryotes as diverse as baker's yeast, mouse ear cress, and blind Mexican cavefish. Hsp90 is a hub of hubs that interacts with many so-called 'client proteins' that affect virtually every aspect of cell signaling and physiology. As Hsp90 facilitates client folding and stability, it can epistatically suppress or enable the expression of genetic variants in its clients and other proteins that acquire client status through mutation. Hsp90's vast interaction network explains the breadth of its phenotypic reach, including Hsp90-dependent de novo mutations and epigenetic effects on gene regulation. Intrinsic links between environmental stress and Hsp90 function thus endow living systems with phenotypic plasticity in fluctuating environments. As environmental perturbations alter Hsp90 function, they also alter Hsp90's interaction with its client proteins, thereby re-wiring networks that determine the genotype-to-phenotype map. Ensuing de-canalization of phenotype creates phenotypic diversity that is not simply stochastic, but often has an underlying genetic basis. Thus, extreme phenotypes can be selected, and assimilated so that they no longer require environmental stress to manifest. In addition to acting on standing genetic variation, Hsp90 perturbation has also been linked to increased frequency of de novo variation and several epigenetic phenomena, all with the potential to generate heritable phenotypic change. Here, we aim to clarify and discuss the multiple means by which Hsp90 can affect phenotype and possibly evolutionary change, and identify their underlying common feature: at its core, Hsp90 interacts epistatically through its chaperone function with many other genes and their gene products. Its influence on phenotypic diversification is thus not magic but rather a fundamental property of genetics.

    View details for PubMedID 29807130

  • It Pays To Be in Phase BIOCHEMISTRY Itakura, A. K., Futia, R. A., Jarosz, D. F. 2018; 57 (17): 2520–29


    To survive, organisms must orchestrate competing biochemical and regulatory processes in time and space. Recent work has suggested that the underlying chemical properties of some biomolecules allow them to self-organize and that life may have exploited this property to organize biochemistry in space and time. Such phase separation is ubiquitous, particularly among the many regulatory proteins that harbor prion-like intrinsically disordered domains. And yet, despite evident regulation by post-translational modification and myriad other stimuli, the biological significance of many phase-separated compartments remains uncertain. Many potential functions have been proposed, but far fewer have been demonstrated. A burgeoning subfield at the intersection of cell biology and polymer physics has defined the biophysical underpinnings that govern the genesis and stability of these particles. The picture is complex: many assemblies are composed of multiple proteins that each have the capacity to phase separate. Here, we briefly discuss this foundational work and survey recent efforts combining targeted biochemical perturbations and quantitative modeling to specifically address the diverse roles that phase separation processes may play in biology.

    View details for DOI 10.1021/acs.biochem.8b00205

    View details for Web of Science ID 000431466700014

    View details for PubMedID 29509425

  • Organizing biochemistry in space and time using prion-like self-assembly. Current opinion in systems biology Jakobson, C. M., Jarosz, D. F. 2018; 8: 16–24


    Prion-like proteins have the capacity to adopt multiple stable conformations, at least one of which can recruit proteins from the native conformation into the alternative fold. Although classically associated with disease, prion-like assembly has recently been proposed to organize a range of normal biochemical processes in space and time. Organisms from bacteria to mammals use prion-like mechanisms to (re)organize their proteome in response to intracellular and extracellular stimuli. Prion-like behavior is an economical means to control biochemistry and gene regulation at the systems level, and prions can act as protein-based genes to facilitate quasi-Lamarckian inheritance of induced traits. These mechanisms allow individual cells to express distinct heritable traits using the same complement of polypeptides. Understanding and controlling prion-like behavior is therefore a promising strategy to combat diverse pathologies and organize engineered biological systems.

    View details for PubMedID 29725624

  • Mapping Causal Variants with Single-Nucleotide Resolution Reveals Biochemical Drivers of Phenotypic Change CELL She, R., Jarosz, D. F. 2018; 172 (3): 478-+


    Understanding the sequence determinants that give rise to diversity among individuals and species is the central challenge of genetics. However, despite ever greater numbers of sequenced genomes, most genome-wide association studies cannot distinguish causal variants from linked passenger mutations spanning many genes. We report that this inherent challenge can be overcome in model organisms. By pushing the advantages of inbred crossing to its practical limit in Saccharomyces cerevisiae, we improved the statistical resolution of linkage analysis to single nucleotides. This "super-resolution" approach allowed us to map 370 causal variants across 26 quantitative traits. Missense, synonymous, and cis-regulatory mutations collectively gave rise to phenotypic diversity, providing mechanistic insight into the basis of evolutionary divergence. Our data also systematically unmasked complex genetic architectures, revealing that multiple closely linked driver mutations frequently act on the same quantitative trait. Single-nucleotide mapping thus complements traditional deletion and overexpression screening paradigms and opens new frontiers in quantitative genetics.

    View details for PubMedID 29373829

    View details for PubMedCentralID PMC5788306

  • Protein-Based Inheritance: Epigenetics beyond the Chromosome MOLECULAR CELL Harvey, Z. H., Chen, Y., Jarosz, D. F. 2018; 69 (2): 195–202


    Epigenetics refers to changes in phenotype that are not rooted in DNA sequence. This phenomenon has largely been studied in the context of chromatin modification. Yet many epigenetic traits are instead linked to self-perpetuating changes in the individual or collective activity of proteins. Most such proteins are prions (e.g., [PSI+], [URE3], [SWI+], [MOT3+], [MPH1+], [LSB+], and [GAR+]), which have the capacity to adopt at least one conformation that self-templates over long biological timescales. This allows them to serve as protein-based epigenetic elements that are readily broadcast through mitosis and meiosis. In some circumstances, self-templating can fuel disease, but it also permits access to multiple activity states from the same polypeptide and transmission of that information across generations. Ensuing phenotypic changes allow genetically identical cells to express diverse and frequently adaptive phenotypes. Although long thought to be rare, protein-based epigenetic inheritance has now been uncovered in all domains of life.

    View details for PubMedID 29153393

    View details for PubMedCentralID PMC5775936

  • Specification of Physiologic and Disease States by Distinct Proteins and Protein Conformations CELL Jarosz, D. F., Khurana, V. 2017; 171 (5): 1001–14


    Protein conformational states-from intrinsically disordered ensembles to amyloids that underlie the self-templating, infectious properties of prion-like proteins-have attracted much attention. Here, we highlight the diversity, including differences in biophysical properties, that drive distinct biological functions and pathologies among self-templating proteins. Advances in chemical genomics, gene editing, and model systems now permit deconstruction of the complex interplay between these protein states and the host factors that react to them. These methods reveal that conformational switches modulate normal and abnormal information transfer and that intimate relationships exist between the intrinsic function of proteins and the deleterious consequences of their misfolding.

    View details for PubMedID 29149602

  • Meeting Report on Experimental Approaches to Evolution and Ecology Using Yeast and Other Model Systems. G3 (Bethesda, Md.) Jarosz, D., Dudley, A. M. 2017


    The fourth EMBO-sponsored conference on Experimental Approaches to Evolution and Ecology Using Yeast and Other Model Systems (, was held at the EMBL in Heidelberg, Germany, October 19-23, 2016. The conference was organized by Judith Berman (Tel Aviv University), Maitreya Dunham (University of Washington), Jun-Yi Leu (Academia Sinica), and Lars Steinmetz (EMBL Heidelberg and Stanford University). The meeting attracted ~120 researchers from 28 countries and covered a wide range of topics in the fields of genetics, evolutionary biology, and ecology with a unifying focus on yeast as a model system. Attendees enjoyed the Keith Haring inspired yeast florescence microscopy artwork (Figure 1), a unique feature of the meeting since its inception, and the one-minute flash talks that catalyzed discussions at two vibrant poster sessions. The meeting coincided with the 20th anniversary of the publication describing the sequence of the first eukaryotic genome, Saccharomyces cerevisiae (Goffeau et al. 1996). Many of the conference talks focused on important questions about what is contained in the genome, how genomes evolve, and the architecture and behavior of communities of phenotypically and genotypically diverse microorganisms. Here, we summarize highlights of the research talks around these themes. Nearly all presentations focused on novel findings, and we refer the reader to relevant manuscripts that have subsequently been published.

    View details for DOI 10.1534/g3.117.300124

    View details for PubMedID 28814445

    View details for PubMedCentralID PMC5633374

  • High-throughput Screening for Protein-based Inheritance in S. cerevisiae JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Byers, J. S., Jarosz, D. F. 2017


    The encoding of biological information that is accessible to future generations is generally achieved via changes to the DNA sequence. Long-lived inheritance encoded in protein conformation (rather than sequence) has long been viewed as paradigm-shifting but rare. The best characterized examples of such epigenetic elements are prions, which possess a self-assembling behavior that can drive the heritable manifestation of new phenotypes. Many archetypal prions display a striking N/Q-rich sequence bias and assemble into an amyloid fold. These unusual features have informed most screening efforts to identify new prion proteins. However, at least three known prions (including the founding prion, PrPSc) do not harbor these biochemical characteristics. We therefore developed an alternative method to probe the scope of protein-based inheritance based on a property of mass action: the transient overexpression of prion proteins increases the frequency at which they acquire a self-templating conformation. This paper describes a method for analyzing the capacity of the yeast ORFeome to elicit protein-based inheritance. Using this strategy, we previously found that >1% of yeast proteins could fuel the emergence of biological traits that were long-lived, stable, and arose more frequently than genetic mutation. This approach can be employed in high throughput across entire ORFeomes or as a targeted screening paradigm for specific genetic networks or environmental stimuli. Just as forward genetic screens define numerous developmental and signaling pathways, these techniques provide a methodology to investigate the influence of protein-based inheritance in biological processes.

    View details for PubMedID 28809826

  • Comprehensive and quantitative mapping of RNA-protein interactions across a transcribed eukaryotic genome PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA She, R., Chakravarty, A. K., Layton, C. J., Chircus, L. M., Andreasson, J. O., Damaraju, N., McMahon, P. L., Buenrostro, J. D., Jarosz, D. F., Greenleaf, W. J. 2017; 114 (14): 3619-3624


    RNA-binding proteins (RBPs) control the fate of nearly every transcript in a cell. However, no existing approach for studying these posttranscriptional gene regulators combines transcriptome-wide throughput and biophysical precision. Here, we describe an assay that accomplishes this. Using commonly available hardware, we built a customizable, open-source platform that leverages the inherent throughput of Illumina technology for direct biophysical measurements. We used the platform to quantitatively measure the binding affinity of the prototypical RBP Vts1 for every transcript in the Saccharomyces cerevisiae genome. The scale and precision of these measurements revealed many previously unknown features of this well-studied RBP. Our transcribed genome array (TGA) assayed both rare and abundant transcripts with equivalent proficiency, revealing hundreds of low-abundance targets missed by previous approaches. These targets regulated diverse biological processes including nutrient sensing and the DNA damage response, and implicated Vts1 in de novo gene "birth." TGA provided single-nucleotide resolution for each binding site and delineated a highly specific sequence and structure motif for Vts1 binding. Changes in transcript levels in vts1Δ cells established the regulatory function of these binding sites. The impact of Vts1 on transcript abundance was largely independent of where it bound within an mRNA, challenging prevailing assumptions about how this RBP drives RNA degradation. TGA thus enables a quantitative description of the relationship between variant RNA structures, affinity, and in vivo phenotype on a transcriptome-wide scale. We anticipate that TGA will provide similarly comprehensive and quantitative insights into the function of virtually any RBP.

    View details for DOI 10.1073/pnas.1618370114

    View details for Web of Science ID 000398159000041

    View details for PubMedID 28325876

  • Old moms say, no Sir. Science (New York, N.Y.) Gitler, A. D., Jarosz, D. F. 2017; 355 (6330): 1126-1127

    View details for DOI 10.1126/science.aam9740

    View details for PubMedID 28302810

  • Amyloid Prions in Fungi. Microbiology spectrum Saupe, S. J., Jarosz, D. F., True, H. L. 2016; 4 (6)


    Prions are infectious protein polymers that have been found to cause fatal diseases in mammals. Prions have also been identified in fungi (yeast and filamentous fungi), where they behave as cytoplasmic non-Mendelian genetic elements. Fungal prions correspond in most cases to fibrillary β-sheet-rich protein aggregates termed amyloids. Fungal prion models and, in particular, yeast prions were instrumental in the description of fundamental aspects of prion structure and propagation. These models established the "protein-only" nature of prions, the physical basis of strain variation, and the role of a variety of chaperones in prion propagation and amyloid aggregate handling. Yeast and fungal prions do not necessarily correspond to harmful entities but can have adaptive roles in these organisms.

    View details for DOI 10.1128/microbiolspec.FUNK-0029-2016

    View details for PubMedID 28087950

  • A common bacterial metabolite elicits prion-based bypass of glucose repression. eLife Garcia, D. M., Dietrich, D., Clardy, J., Jarosz, D. F. 2016; 5


    Robust preference for fermentative glucose metabolism has motivated domestication of the budding yeast Saccharomyces cerevisiae. This program can be circumvented by a protein-based genetic element, the [GAR(+)] prion, permitting simultaneous metabolism of glucose and other carbon sources. Diverse bacteria can elicit yeast cells to acquire [GAR(+)], although the molecular details of this interaction remain unknown. Here we identify the common bacterial metabolite lactic acid as a strong [GAR(+)] inducer. Transient exposure to lactic acid caused yeast cells to heritably circumvent glucose repression. This trait had the defining genetic properties of [GAR(+)], and did not require utilization of lactic acid as a carbon source. Lactic acid also induced [GAR(+)]-like epigenetic states in fungi that diverged from S. cerevisiae ~200 million years ago, and in which glucose repression evolved independently. To our knowledge, this is the first study to uncover a bacterial metabolite with the capacity to potently induce a prion.

    View details for DOI 10.7554/eLife.17978

    View details for PubMedID 27906649

    View details for PubMedCentralID PMC5132342

  • Intrinsically Disordered Proteins Drive Emergence and Inheritance of Biological Traits. Cell Chakrabortee, S., Byers, J. S., Jones, S., Garcia, D. M., Bhullar, B., Chang, A., She, R., Lee, L., Fremin, B., Lindquist, S., Jarosz, D. F. 2016; 167 (2): 369-381 e12


    Prions are a paradigm-shifting mechanism of inheritance in which phenotypes are encoded by self-templating protein conformations rather than nucleic acids. Here, we examine the breadth of protein-based inheritance across the yeast proteome by assessing the ability of nearly every open reading frame (ORF; ∼5,300 ORFs) to induce heritable traits. Transient overexpression of nearly 50 proteins created traits that remained heritable long after their expression returned to normal. These traits were beneficial, had prion-like patterns of inheritance, were common in wild yeasts, and could be transmitted to naive cells with protein alone. Most inducing proteins were not known prions and did not form amyloid. Instead, they are highly enriched in nucleic acid binding proteins with large intrinsically disordered domains that have been widely conserved across evolution. Thus, our data establish a common type of protein-based inheritance through which intrinsically disordered proteins can drive the emergence of new traits and adaptive opportunities.

    View details for DOI 10.1016/j.cell.2016.09.017

    View details for PubMedID 27693355

    View details for PubMedCentralID PMC5066306

  • Hsp90: A Global Regulator of the Genotype-to-Phenotype Map in Cancers. Advances in cancer research Jarosz, D. 2016; 129: 225-247


    Cancer cells have the unusual capacity to limit the cost of the mutation load that they harbor and simultaneously harness its evolutionary potential. This property fuels drug resistance, a key failure mode in oncogene-directed therapy. However, the factors that regulate this capacity might also provide an Achilles' heel that could be exploited therapeutically. Recently, insight has come from a seemingly distant field: protein folding. It is now clear that protein homeostasis broadly supports malignancy and fuels the rapid evolution of drug resistance. Among protein homeostatic mechanisms that influence cancer biology, the essential ATP-driven molecular chaperone heat-shock protein 90 (Hsp90) is especially important. Hsp90 catalyzes folding of many proteins that regulate growth and development. These "client" kinases, transcription factors, and ubiquitin ligases often play critical roles in human disease, especially cancer. Studies in a wide range of systems-from single-celled organisms to human tumor samples-suggest that Hsp90 can broadly reshape the map between genotype and phenotype, acting as a "capacitor" and "potentiator" of genetic variation. Indeed, it has likely done so to such a degree that it has left an impress on diverse genome sequences. Hsp90 can constitute as much as 5% of total protein in transformed cells and increased levels of heat-shock activation correlate with poor prognosis in breast cancer. These findings and others have motivated a flurry of interest in Hsp90 inhibitors as cancer therapeutics, which have met with rather limited success as single agents, but may eventually prove invaluable in limiting the emergence of resistance to other chemotherapeutics, both genotoxic and molecularly targeted. Here, we provide an overview of Hsp90 function, review its relationship to genetic variation and the evolution of new traits, and discuss the importance of these findings for cancer biology and future efforts to drug this pathway.

    View details for DOI 10.1016/bs.acr.2015.11.001

    View details for PubMedID 26916007

  • Cross-kingdom chemical communication drives a heritable, mutually beneficial prion-based transformation of metabolism. Cell Jarosz, D. F., Brown, J. C., Walker, G. A., Datta, M. S., Ung, W. L., Lancaster, A. K., Rotem, A., Chang, A., Newby, G. A., Weitz, D. A., Bisson, L. F., Lindquist, S. 2014; 158 (5): 1083-1093


    In experimental science, organisms are usually studied in isolation, but in the wild, they compete and cooperate in complex communities. We report a system for cross-kingdom communication by which bacteria heritably transform yeast metabolism. An ancient biological circuit blocks yeast from using other carbon sources in the presence of glucose. [GAR(+)], a protein-based epigenetic element, allows yeast to circumvent this "glucose repression" and use multiple carbon sources in the presence of glucose. Some bacteria secrete a chemical factor that induces [GAR(+)]. [GAR(+)] is advantageous to bacteria because yeast cells make less ethanol and is advantageous to yeast because their growth and long-term viability is improved in complex carbon sources. This cross-kingdom communication is broadly conserved, providing a compelling argument for its adaptive value. By heritably transforming growth and survival strategies in response to the selective pressures of life in a biological community, [GAR(+)] presents a unique example of Lamarckian inheritance.

    View details for DOI 10.1016/j.cell.2014.07.025

    View details for PubMedID 25171409

  • An Evolutionarily Conserved Prion-like Element Converts Wild Fungi from Metabolic Specialists to Generalists. Cell Jarosz, D. F., Lancaster, A. K., Brown, J. C., Lindquist, S. 2014; 158 (5): 1072-1082


    [GAR(+)] is a protein-based element of inheritance that allows yeast (Saccharomyces cerevisiae) to circumvent a hallmark of their biology: extreme metabolic specialization for glucose fermentation. When glucose is present, yeast will not use other carbon sources. [GAR(+)] allows cells to circumvent this "glucose repression." [GAR(+)] is induced in yeast by a factor secreted by bacteria inhabiting their environment. We report that de novo rates of [GAR(+)] appearance correlate with the yeast's ecological niche. Evolutionarily distant fungi possess similar epigenetic elements that are also induced by bacteria. As expected for a mechanism whose adaptive value originates from the selective pressures of life in biological communities, the ability of bacteria to induce [GAR(+)] and the ability of yeast to respond to bacterial signals have been extinguished repeatedly during the extended monoculture of domestication. Thus, [GAR(+)] is a broadly conserved adaptive strategy that links environmental and social cues to heritable changes in metabolism.

    View details for DOI 10.1016/j.cell.2014.07.024

    View details for PubMedID 25171408

  • Pernicious pathogens or expedient elements of inheritance: the significance of yeast prions. PLoS pathogens Byers, J. S., Jarosz, D. F. 2014; 10 (4)

    View details for DOI 10.1371/journal.ppat.1003992

    View details for PubMedID 24722628

  • Pernicious pathogens or expedient elements of inheritance: the significance of yeast prions. PLoS pathogens Byers, J. S., Jarosz, D. F. 2014; 10 (4)

    View details for DOI 10.1371/journal.ppat.1003992

    View details for PubMedID 24722628

    View details for PubMedCentralID PMC3983059

  • Rebels with a cause: molecular features and physiological consequences of yeast prions FEMS YEAST RESEARCH Garcia, D. M., Jarosz, D. F. 2014; 14 (1): 136-147


    Prions are proteins that convert between structurally and functionally distinct states, at least one of which is self-perpetuating. The prion fold templates the conversion of native protein, altering its structure and function, and thus serves as a protein-based element of inheritance. Molecular chaperones ensure that these prion aggregates are divided and faithfully passed from mother cells to their daughters. Prions were originally identified as the cause of several rare neurodegenerative diseases in mammals, but the last decade has brought great progress in understanding their broad importance in biology and evolution. Most prion proteins regulate information flow in signaling networks, or otherwise affect gene expression. Consequently, switching into and out of prion states creates diverse new traits – heritable changes based on protein structure rather than nucleic acid. Despite intense study of the molecular mechanisms of this paradigm-shifting, epigenetic mode of inheritance, many key questions remain. Recent studies in yeast that support the view that prions are common, often beneficial elements of inheritance that link environmental stress to the appearance of new traits.

    View details for DOI 10.1111/1567-1364.12116

    View details for Web of Science ID 000330816300013

  • Cryptic Variation in Morphological Evolution: HSP90 as a Capacitor for Loss of Eyes in Cavefish SCIENCE Rohner, N., Jarosz, D. F., Kowalko, J. E., Yoshizawa, M., Jeffery, W. R., Borowsky, R. L., Lindquist, S., Tabin, C. J. 2013; 342 (6164): 1372-1375


    In the process of morphological evolution, the extent to which cryptic, preexisting variation provides a substrate for natural selection has been controversial. We provide evidence that heat shock protein 90 (HSP90) phenotypically masks standing eye-size variation in surface populations of the cavefish Astyanax mexicanus. This variation is exposed by HSP90 inhibition and can be selected for, ultimately yielding a reduced-eye phenotype even in the presence of full HSP90 activity. Raising surface fish under conditions found in caves taxes the HSP90 system, unmasking the same phenotypic variation as does direct inhibition of HSP90. These results suggest that cryptic variation played a role in the evolution of eye loss in cavefish and provide the first evidence for HSP90 as a capacitor for morphological evolution in a natural setting.

    View details for DOI 10.1126/science.1240276

    View details for Web of Science ID 000328196000051

    View details for PubMedID 24337296

  • Prions are a common mechanism for phenotypic inheritance in wild yeasts NATURE Halfmann, R., Jarosz, D. F., Jones, S. K., Chang, A., Lancaster, A. K., Lindquist, S. 2012; 482 (7385): 363-U1507


    The self-templating conformations of yeast prion proteins act as epigenetic elements of inheritance. Yeast prions might provide a mechanism for generating heritable phenotypic diversity that promotes survival in fluctuating environments and the evolution of new traits. However, this hypothesis is highly controversial. Prions that create new traits have not been found in wild strains, leading to the perception that they are rare 'diseases' of laboratory cultivation. Here we biochemically test approximately 700 wild strains of Saccharomyces for [PSI(+)] or [MOT3(+)], and find these prions in many. They conferred diverse phenotypes that were frequently beneficial under selective conditions. Simple meiotic re-assortment of the variation harboured within a strain readily fixed one such trait, making it robust and prion-independent. Finally, we genetically screened for unknown prion elements. Fully one-third of wild strains harboured them. These, too, created diverse, often beneficial phenotypes. Thus, prions broadly govern heritable traits in nature, in a manner that could profoundly expand adaptive opportunities.

    View details for DOI 10.1038/nature10875

    View details for Web of Science ID 000300287100038

    View details for PubMedID 22337056

  • Hsp90 and Environmental Stress Transform the Adaptive Value of Natural Genetic Variation SCIENCE Jarosz, D. F., Lindquist, S. 2010; 330 (6012): 1820-1824


    How can species remain unaltered for long periods yet also undergo rapid diversification? By linking genetic variation to phenotypic variation via environmental stress, the Hsp90 protein-folding reservoir might promote both stasis and change. However, the nature and adaptive value of Hsp90-contingent traits remain uncertain. In ecologically and genetically diverse yeasts, we find such traits to be both common and frequently adaptive. Most are based on preexisting variation, with causative polymorphisms occurring in coding and regulatory sequences alike. A common temperature stress alters phenotypes similarly. Both selective inhibition of Hsp90 and temperature stress increase correlations between genotype and phenotype. This system broadly determines the adaptive value of standing genetic variation and, in so doing, has influenced the evolution of current genomes.

    View details for DOI 10.1126/science.1195487

    View details for Web of Science ID 000285603700040

    View details for PubMedID 21205668

  • HSP90 at the hub of protein homeostasis: emerging mechanistic insights NATURE REVIEWS MOLECULAR CELL BIOLOGY Taipale, M., Jarosz, D. F., Lindquist, S. 2010; 11 (7): 515-528


    Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that facilitates the maturation of a wide range of proteins (known as clients). Clients are enriched in signal transducers, including kinases and transcription factors. Therefore, HSP90 regulates diverse cellular functions and exerts marked effects on normal biology, disease and evolutionary processes. Recent structural and functional analyses have provided new insights on the transcriptional and biochemical regulation of HSP90 and the structural dynamics it uses to act on a diverse client repertoire. Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.

    View details for DOI 10.1038/nrm2918

    View details for Web of Science ID 000280076000016

    View details for PubMedID 20531426

  • Protein Homeostasis and the Phenotypic Manifestation of Genetic Diversity: Principles and Mechanisms ANNUAL REVIEW OF GENETICS, VOL 44 Jarosz, D. F., Taipale, M., Lindquist, S. 2010; 44: 189-216


    Changing a single nucleotide in a genome can have profound consequences under some conditions, but the same change can have no consequences under others. Indeed, organisms can be surprisingly robust to environmental and genetic perturbations. Yet, the mechanisms underlying such robustness are controversial. Moreover, how they might affect evolutionary change remains enigmatic. Here, we review the recently appreciated central role of protein homeostasis in buffering and potentiating genetic variation and discuss how these processes mediate the critical influence of the environment on the relationship between genotype and phenotype. Deciphering how robustness emerges from biological organization and the mechanisms by which it is overcome in changing environments will lead to a more complete understanding of both fundamental evolutionary processes and diverse human diseases.

    View details for DOI 10.1146/annurev.genet.40.110405.090412

    View details for Web of Science ID 000286042600009

    View details for PubMedID 21047258

  • A DinB variant reveals diverse physiological consequences of incomplete TLS extension by a Y-family DNA polymerase PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Jarosz, D. F., Cohen, S. E., Delaney, J. C., Essigmann, J. M., Walker, G. C. 2009; 106 (50): 21137-21142


    The only Y-family DNA polymerase conserved among all domains of life, DinB and its mammalian ortholog pol kappa, catalyzes proficient bypass of damaged DNA in translesion synthesis (TLS). Y-family DNA polymerases, including DinB, have been implicated in diverse biological phenomena ranging from adaptive mutagenesis in bacteria to several human cancers. Complete TLS requires dNTP insertion opposite a replication blocking lesion and subsequent extension with several dNTP additions. Here we report remarkably proficient TLS extension by DinB from Escherichia coli. We also describe a TLS DNA polymerase variant generated by mutation of an evolutionarily conserved tyrosine (Y79). This mutant DinB protein is capable of catalyzing dNTP insertion opposite a replication-blocking lesion, but cannot complete TLS, stalling three nucleotides after an N(2)-dG adduct. Strikingly, expression of this variant transforms a bacteriostatic DNA damaging agent into a bactericidal drug, resulting in profound toxicity even in a dinB(+) background. We find that this phenomenon is not exclusively due to a futile cycle of abortive TLS followed by exonucleolytic reversal. Rather, gene products with roles in cell death and metal homeostasis modulate the toxicity of DinB(Y79L) expression. Together, these results indicate that DinB is specialized to perform remarkably proficient insertion and extension on damaged DNA, and also expose unexpected connections between TLS and cell fate.

    View details for DOI 10.1073/pnas.0907257106

    View details for Web of Science ID 000272795300025

    View details for PubMedID 19948952

    View details for PubMedCentralID PMC2795518

  • Song: SOS (To the Tune of ABBA's "SOS"). Biochemistry and molecular biology education Simon, S. M., Waters, L. S., Jarosz, D. F., Beuning, P. J. 2009; 37 (5): 316-?

    View details for DOI 10.1002/bmb.20305

    View details for PubMedID 21567763

  • UmuD and RecA directly modulate the mutagenic potential of the Y family DNA polymerase DinB MOLECULAR CELL Godoy, V. G., Jarosz, D. F., Simon, S. M., Abyzov, A., Ilyin, V., Walker, G. C. 2007; 28 (6): 1058-1070


    DinB is the only translesion Y family DNA polymerase conserved among bacteria, archaea, and eukaryotes. DinB and its orthologs possess a specialized lesion bypass function but also display potentially deleterious -1 frameshift mutagenic phenotypes when overproduced. We show that the DNA damage-inducible proteins UmuD(2) and RecA act in concert to modulate this mutagenic activity. Structural modeling suggests that the relatively open active site of DinB is enclosed by interaction with these proteins, thereby preventing the template bulging responsible for -1 frameshift mutagenesis. Intriguingly, residues that define the UmuD(2)-interacting surface on DinB statistically covary throughout evolution, suggesting a driving force for the maintenance of a regulatory protein-protein interaction at this site. Together, these observations indicate that proteins like RecA and UmuD(2) may be responsible for managing the mutagenic potential of DinB orthologs throughout evolution.

    View details for DOI 10.1016/j.molcel.2007.10.025

    View details for Web of Science ID 000252170000012

    View details for PubMedID 18158902

    View details for PubMedCentralID PMC2265384

  • DNA polymerase V allows bypass of toxic guanine oxidation products in vivo JOURNAL OF BIOLOGICAL CHEMISTRY Neeley, W. L., Delaney, S., Alekseyev, Y. O., Jarosz, D. F., Delaney, J. C., Walker, G. C., Essigmann, J. M. 2007; 282 (17): 12741-12748


    Reactive oxygen and nitrogen radicals produced during metabolic processes, such as respiration and inflammation, combine with DNA to form many lesions primarily at guanine sites. Understanding the roles of the polymerases responsible for the processing of these products to mutations could illuminate molecular mechanisms that correlate oxidative stress with cancer. Using M13 viral genomes engineered to contain single DNA lesions and Escherichia coli strains with specific polymerase (pol) knockouts, we show that pol V is required for efficient bypass of structurally diverse, highly mutagenic guanine oxidation products in vivo. We also find that pol IV participates in the bypass of two spiroiminodihydantoin lesions. Furthermore, we report that one lesion, 5-guanidino-4-nitroimidazole, is a substrate for multiple SOS polymerases, whereby pol II is necessary for error-free replication and pol V for error-prone replication past this lesion. The results spotlight a major role for pol V and minor roles for pol II and pol IV in the mechanism of guanine oxidation mutagenesis.

    View details for DOI 10.1074/jbc.M700575200

    View details for Web of Science ID 000245942800044

    View details for PubMedID 17322566

  • Proficient and accurate bypass of persistent DNA lesions by DinB DNA polymerases CELL CYCLE Jarosz, D. F., Godoy, V. G., Walker, G. C. 2007; 6 (7): 817-822


    Despite nearly universal conservation through evolution, the precise function of the DinB/pol kappa branch of the Y-family of DNA polymerases has remained unclear. Recent results suggest that DinB orthologs from all domains of life proficiently bypass replication blocking lesions that may be recalcitrant to DNA repair mechanisms. Like other translesion DNA polymerases, the error frequency of DinB and its orthologs is higher than the DNA polymerases that replicate the majority of the genome. However, recent results suggest that some Y-family polymerases, including DinB and pol kappa, bypass certain types of DNA damage with greater proficiency than an undamaged template. Moreover, they do so relatively accurately. The ability to employ this mechanism to manage DNA damage may be especially important for types of DNA modification that elude repair mechanisms. For these lesions, translesion synthesis may represent a more important line of defense than for other types of DNA damage that are more easily dealt with by other more accurate mechanisms.

    View details for Web of Science ID 000245577800012

    View details for PubMedID 17377496

  • Y-family DNA polymerases in Escherichia coli TRENDS IN MICROBIOLOGY Jarosz, D. F., Beuning, P. J., Cohen, S. E., Walker, G. C. 2007; 15 (2): 70-77


    The observation that mutations in the Escherichia coli genes umuC+ and umuD+ abolish mutagenesis induced by UV light strongly supported the counterintuitive notion that such mutagenesis is an active rather than passive process. Genetic and biochemical studies have revealed that umuC+ and its homolog dinB+ encode novel DNA polymerases with the ability to catalyze synthesis past DNA lesions that otherwise stall replication--a process termed translesion synthesis (TLS). Similar polymerases have been identified in nearly all organisms, constituting a new enzyme superfamily. Although typically viewed as unfaithful copiers of DNA, recent studies suggest that certain TLS polymerases can perform proficient and moderately accurate bypass of particular types of DNA damage. Moreover, various cellular factors can modulate their activity and mutagenic potential.

    View details for DOI 10.1016/j.tim.2006.12.004

    View details for Web of Science ID 000244535900004

    View details for PubMedID 17207624

  • Y-family DNA polymerases respond to DNA damage-independent inhibition of replication fork progression EMBO JOURNAL Godoy, V. G., Jarosz, D. F., Walker, F. L., Simmons, L. A., Walker, G. C. 2006; 25 (4): 868-879


    In Escherichia coli, the Y-family DNA polymerases Pol IV (DinB) and Pol V (UmuD2'C) enhance cell survival upon DNA damage by bypassing replication-blocking DNA lesions. We report a unique function for these polymerases when DNA replication fork progression is arrested not by exogenous DNA damage, but with hydroxyurea (HU), thereby inhibiting ribonucleotide reductase, and bringing about damage-independent DNA replication stalling. Remarkably, the umuC122::Tn5 allele of umuC, dinB, and certain forms of umuD gene products endow E. coli with the ability to withstand HU treatment (HUR). The catalytic activities of the UmuC122 and DinB proteins are both required for HUR. Moreover, the lethality brought about by such stalled replication forks in the wild-type derivatives appears to proceed through the toxin/antitoxin pairs mazEF and relBE. This novel function reveals a role for Y-family polymerases in enhancing cell survival under conditions of nucleotide starvation, in addition to their established functions in response to DNA damage.

    View details for DOI 10.1038/sj.emboj.7600986

    View details for Web of Science ID 000236225000020

    View details for PubMedID 16482223

    View details for PubMedCentralID PMC1383567

  • A single amino acid governs enhanced activity of DinB DNA polymerases on damaged templates NATURE Jarosz, D. F., Godoy, V. G., Delaney, J. C., Essigmann, J. M., Walker, G. C. 2006; 439 (7073): 225-228


    Translesion synthesis (TLS) by Y-family DNA polymerases is a chief mechanism of DNA damage tolerance. Such TLS can be accurate or error-prone, as it is for bypass of a cyclobutane pyrimidine dimer by DNA polymerase eta (XP-V or Rad30) or bypass of a (6-4) TT photoproduct by DNA polymerase V (UmuD'2C), respectively. Although DinB is the only Y-family DNA polymerase conserved among all domains of life, the biological rationale for this striking conservation has remained enigmatic. Here we report that the Escherichia coli dinB gene is required for resistance to some DNA-damaging agents that form adducts at the N2-position of deoxyguanosine (dG). We show that DinB (DNA polymerase IV) catalyses accurate TLS over one such N2-dG adduct (N2-furfuryl-dG), and that DinB and its mammalian orthologue, DNA polymerase kappa, insert deoxycytidine (dC) opposite N2-furfuryl-dG with 10-15-fold greater catalytic proficiency than opposite undamaged dG. We also show that mutating a single amino acid, the 'steric gate' residue of DinB (Phe13 --> Val) and that of its archaeal homologue Dbh (Phe12 --> Ala), separates the abilities of these enzymes to perform TLS over N2-dG adducts from their abilities to replicate an undamaged template. We propose that DinB and its orthologues are specialized to catalyse relatively accurate TLS over some N2-dG adducts that are ubiquitous in nature, that lesion bypass occurs more efficiently than synthesis on undamaged DNA, and that this specificity may be achieved at least in part through a lesion-induced conformational change.

    View details for DOI 10.1038/nature04318

    View details for Web of Science ID 000234538400045

    View details for PubMedID 16407906

  • Characterization of Escherichia coli translesion synthesis polymerases and their accessory factors DNA REPAIR, PT A Beuning, P. J., Simon, S. M., Godoy, V. G., Jarosz, D. F., Walker, G. C. 2006; 408: 318-340


    Members of the Y family of DNA polymerases are specialized to replicate lesion-containing DNA. However, they lack 3'-5' exonuclease activity and have reduced fidelity compared to replicative polymerases when copying undamaged templates, and thus are potentially mutagenic. Y family polymerases must be tightly regulated to prevent aberrant mutations on undamaged DNA while permitting replication only under conditions of DNA damage. These polymerases provide a mechanism of DNA damage tolerance, confer cellular resistance to a variety of DNA-damaging agents, and have been implicated in bacterial persistence. The Y family polymerases are represented in all domains of life. Escherichia coli possesses two members of the Y family, DNA pol IV (DinB) and DNA pol V (UmuD'(2)C), and several regulatory factors, including those encoded by the umuD gene that influence the activity of UmuC. This chapter outlines procedures for in vivo and in vitro analysis of these proteins. Study of the E. coli Y family polymerases and their accessory factors is important for understanding the broad principles of DNA damage tolerance and mechanisms of mutagenesis throughout evolution. Furthermore, study of these enzymes and their role in stress-induced mutagenesis may also give insight into a variety of phenomena, including the growing problem of bacterial antibiotic resistance.

    View details for DOI 10.1016/S0076-6879(06)08020-7

    View details for Web of Science ID 000238224100020

    View details for PubMedID 16793378