Academic Appointments

Professional Education

  • PhD, Cornell University, Biochemistry, Molecular, and Cell Biology (2019)

All Publications

  • The proportional scaling of mRNA and ribosome concentrations controls eukaryotic cell growth. Nature cell biology Gao, X., Lanz, M., Grosely, R., Cremer, J., Puglisi, J., Skotheim, J. M. 2026

    Abstract

    Cell growth underlies nearly all eukaryotic physiology, yet its quantitative principles remain unclear. Here, using single-molecule ribosome tracking, spike-in RNA sequencing and quantitative proteomics across 15 nutrient-limited conditions in budding yeast, we define how growth is controlled in the budding yeast Saccharomyces cerevisiae. Ribosome concentration scales linearly with growth rate, while peptide elongation speed remains constant at approximately nine amino acids per second. While elongation is not a regulatory lever, total mRNA concentration increases proportionally with ribosomes to accelerate growth. A simple kinetic model of mRNA-ribosome binding accurately predicts the fraction of active ribosomes, growth rate and responses to transcriptional or size perturbations. Consistent with this model, transient inhibition of mRNA degradation boosts growth by elevating mRNA concentration. These results reveal that eukaryotic cells accelerate proliferation primarily by proportionally scaling mRNA and ribosome abundance, establishing a quantitative framework for understanding eukaryotic biosynthesis.

    View details for DOI 10.1038/s41556-026-02045-0

    View details for PubMedID 42642654

  • Cell size-dependent mRNA transcription drives proteome remodeling. Cell reports You, D. S., Bohrer, C. H., Rumde, P. H., Sanidas, I., Swaffer, M. P., Larson, D. R., Elias, J. E., Lanz, M. C., Skotheim, J. M. 2026; 45 (6): 117488

    Abstract

    Increasing cell size drives proteomic changes that impact cell physiology. However, the molecular basis of size-dependent proteome remodeling has remained unclear. Here, we develop an inducible Cyclin D1 expression system in human cells to generate proliferating cells spanning over a 2-fold size range. We use this system to make comprehensive genome-wide measurements of mRNA and protein concentrations and stability. We find that protein and mRNA turnover rates are weakly related to cell size but that mRNA concentrations are strongly size-dependent. This establishes that transcriptional regulation is the basis of proteome remodeling. Live-cell imaging of nascent mRNAs using the MS2 system is used to measure how transcriptional dynamics change with cell size. Larger cells prolong transcriptional bursts but maintain similar burst amplitudes to achieve transcriptional scaling. Together, our results show how transcription is modulated by cell size to remodel the proteome and alter cell physiology.

    View details for DOI 10.1016/j.celrep.2026.117488

    View details for PubMedID 42275220

  • Chromatin association promotes UBR5-mediated degradation of Rb. bioRxiv : the preprint server for biology Zhang, S., Lanz, M. C., Konschnik, J., Skotheim, J. M. 2026

    Abstract

    The retinoblastoma protein Rb is a cell cycle inhibitor that plays a central role in regulating the G1/S cell cycle transition. Un-/hypo-phosphorylated Rb suppresses E2F transcription activity by binding to E2F/DP dimers and recruiting chromatin remodelers to prevent cells from entering S phase. For cells to progress through the G1/S transition, Rb is inactivated by two mechanisms: the "classic" pathway of Rb hyperphosphorylation by Cyclin-CDK complexes, and a recently identified "degradation" mechanism driven by the E3 ubiquitin ligase UBR5. These two pathways are interconnected, as only the un-/hypo-phosphorylated Rb can be degraded, and the hyper-phosphorylated Rb is stabilized to promote its reaccumulation in preparation for the next cell division cycle. However, the molecular basis for how Rb is stabilized upon phosphorylation remains unclear. In this study, we found that UBR5 preferentially targets chromatin-associated proteins for degradation. Since Rb's chromatin association is modulated by its phosphorylation, we hypothesized that phosphorylation may affect Rb stability by altering its chromatin association. To test this, we constructed a series of un-phosphorylatable Rb variants with graded reductions in chromatin association. Consistent with our hypothesis, we observed a strong correlation between an Rb variant's chromatin association and its half-life. Fusing these Rb variants to histone H1 increased chromatin association to similar levels and equalized their protein half-lives. Taken together, these findings show how phosphorylation stabilizes Rb by promoting its dissociation from chromatin. This provides a striking example for how sub-organellar protein localization may be used to regulate stability.

    View details for DOI 10.64898/2026.04.16.719064

    View details for PubMedID 42039660

    View details for PubMedCentralID PMC13104884

  • Cell enlargement drives aging-associated proteome remodeling and shortens replicative lifespan. bioRxiv : the preprint server for biology Lanz, M. C., Hotz, M., Kroll-Ling, R., Wang, E., Kim, J., Elias, J. E., Gottschling, D. E., Skotheim, J. M. 2026

    Abstract

    The molecular and cellular basis of aging and its associated functional decline remains poorly understood. Even free-living microorganisms age and, in yeast, replicative aging shares key hallmarks with human cellular senescence, including progressive cell enlargement. Recent work has shown that chemical and genetic manipulations that increase cell size promote the onset of senescence in both yeast and human cells, suggesting that cell enlargement can drive some of the physiological changes associated with aging. Here, we quantitatively determined how cell enlargement contributes to age-associated physiology in yeast by combining automated aging technologies with quantitative proteomics. We find that the majority of aging-associated proteome remodeling can be recapitulated by genetically enlarging young proliferating cells. These enlarged cells exhibit accelerated proteome aging and shortened replicative lifespans, while smaller cells are longer-lived. While cell enlargement is the predominant factor driving proteome remodeling during aging, we also identified a minority of aging-specific molecular markers whose expression influences lifespan. Together, our results demonstrate that cell enlargement is a major driver of aging-associated proteome remodeling and influences lifespan independently of established aging factors such as extrachromosomal rDNA circles.

    View details for DOI 10.64898/2026.02.15.706013

    View details for PubMedID 41757022

    View details for PubMedCentralID PMC12934684

  • Identification and inhibition of the Cyclin D Rb-docking interface that drives cell division. bioRxiv : the preprint server for biology Topacio, B. R., Fleming, C. B., Lanz, M. C., Zhang, S., Xie, S., Tuvikene, J., Weaver, A., Sanidas, I., Sage, J., Rubin, S. M., Kõivomägi, M., Skotheim, J. M. 2026

    Abstract

    The animal cell division cycle is initiated by the cyclin-dependent kinases CDK4 and CDK6 in complex with D-type cyclins. Cyclin D-CDK4/6 complex formation is promoted by the assembly factors p21 and p27, which bind both subunits. p27 binds the hydrophobic patch on cyclin D that is similar to the patch used by other cell cycle cyclins to dock their substrates. This raised the question as to how cyclin D could find its substrates if its hydrophobic patch were already occupied? Here, we show that D-type cyclins use their A2' helix to dock the retinoblastoma protein Rb, a key substrate regulating cell cycle progression. The specific interface of cyclin D's A2' helix is unique among cyclins and its mutation slows proliferation. Taken together, our work identifies a cyclin D-substrate docking mechanism that can be targeted by novel cancer therapeutics.

    View details for DOI 10.64898/2026.01.14.699544

    View details for PubMedID 41648226

    View details for PubMedCentralID PMC12871278

  • Maintenance of cytoplasmic and membrane densities shapes cellular geometry in Escherichia coli. Nature communications Chure, G., de Silva, R. T., Sharma, R., Lanz, M. C., Cremer, J. 2025

    Abstract

    Microbes precisely control their composition and geometry across diverse growth conditions, yet the mechanisms coordinating these processes remain unclear. Here, we integrate quantitative proteomics, microscopy, and biochemical measurements to reveal a biophysical principle linking these properties in Escherichia coli: cytoplasmic and membrane protein densities maintain a tightly conserved ratio across growth conditions, while the periplasmic density varies. Building on this observation, we develop a mathematical model demonstrating that maintaining this density ratio constrains the surface-to-volume ratio as a nonlinear function of proteome composition, specifically the ribosomal proteome fraction and partitioning between cellular compartments. The model holds under guanosine tetraphosphate perturbations that alter ribosome levels, further demonstrating that cellular geometry is not strictly determined by growth rate. These findings provide a biophysical framework for geometry control, underscoring density maintenance as a key physiological constraint that shapes cellular phenotypes.

    View details for DOI 10.1038/s41467-025-67553-3

    View details for PubMedID 41429793

  • Intracellular diffusion in the cytoplasm increases with cell size in fission yeast MOLECULAR BIOLOGY OF THE CELL Tan, C., Lanz, M. C., Swaffer, M., Skotheim, J., Chang, F. 2025; 36 (4): 1-13

    View details for Web of Science ID 001463439400001

  • Intracellular diffusion in the cytoplasm increases with cell size in fission yeast. Molecular biology of the cell Tan, C., Lanz, M. C., Swaffer, M., Skotheim, J., Chang, F. 2025: mbcE24110488

    Abstract

    Diffusion in the cytoplasm can greatly impact cellular processes, yet regulation of macromolecular diffusion remains poorly understood. There is increasing evidence that cell size affects the density and macromolecular composition of the cytoplasm. Here, we studied whether cell size affects diffusion at the scale of macromolecules tens of microns in diameter. We analyzed the diffusive motions of intracellular genetically-encoded multimeric 40 nm nanoparticles (cytGEMs) in the cytoplasm of the fission yeast Schizosaccharomyces pombe. Using cell size mutants, we showed that cytGEMs diffusion coefficients decreased in smaller cells and increased in larger cells. This increase in diffusion in large cells may be due to a decrease in the DNA-to-Cytoplasm ratio, as diffusion was not affected in large multinucleate cytokinesis mutant cells. In investigating the underlying causes of altered cytGEMs diffusion, we found that the proteomes of large and small cells exhibited size-specific changes, including the sub-scaling of ribosomal proteins in large cells. Comparison with a similar dataset from human cells revealed that features of size-dependent proteome remodeling were conserved. These studies demonstrate that cell size is an important parameter in determining the biophysical properties and the composition of the cytoplasm.

    View details for DOI 10.1091/mbc.E24-11-0488

    View details for PubMedID 39969966

  • Genome concentration limits cell growth and modulates proteome composition in Escherichia coli. eLife Mäkelä, J., Papagiannakis, A., Lin, W. H., Lanz, M. C., Glenn, S., Swaffer, M., Marinov, G. K., Skotheim, J. M., Jacobs-Wagner, C. 2024; 13

    Abstract

    Defining the cellular factors that drive growth rate and proteome composition is essential for understanding and manipulating cellular systems. In bacteria, ribosome concentration is known to be a constraining factor of cell growth rate, while gene concentration is usually assumed not to be limiting. Here, using single-molecule tracking, quantitative single-cell microscopy, and modeling, we show that genome dilution in Escherichia coli cells arrested for DNA replication limits total RNA polymerase activity within physiological cell sizes across tested nutrient conditions. This rapid-onset limitation on bulk transcription results in sub-linear scaling of total active ribosomes with cell size and sub-exponential growth. Such downstream effects on bulk translation and cell growth are near-immediately detectable in a nutrient-rich medium, but delayed in nutrient-poor conditions, presumably due to cellular buffering activities. RNA sequencing and tandem-mass-tag mass spectrometry experiments further reveal that genome dilution remodels the relative abundance of mRNAs and proteins with cell size at a global level. Altogether, our findings indicate that chromosome concentration is a limiting factor of transcription and a global modulator of the transcriptome and proteome composition in E. coli. Experiments in Caulobacter crescentus and comparison with eukaryotic cell studies identify broadly conserved DNA concentration-dependent scaling principles of gene expression.

    View details for DOI 10.7554/eLife.97465

    View details for PubMedID 39714909

    View details for PubMedCentralID PMC11666246

  • Genome dilution by cell growth drives starvation-like proteome remodeling in mammalian and yeast cells. Nature structural & molecular biology Lanz, M. C., Zhang, S., Swaffer, M. P., Ziv, I., Gotz, L. H., Kim, J., McCarthy, F., Jarosz, D. F., Elias, J. E., Skotheim, J. M. 2024

    Abstract

    Cell size is tightly controlled in healthy tissues and single-celled organisms, but it remains unclear how cell size influences physiology. Increasing cell size was recently shown to remodel the proteomes of cultured human cells, demonstrating that large and small cells of the same type can be compositionally different. In the present study, we utilize the natural heterogeneity of hepatocyte ploidy and yeast genetics to establish that the ploidy-to-cell size ratio is a highly conserved determinant of proteome composition. In both mammalian and yeast cells, genome dilution by cell growth elicits a starvation-like phenotype, suggesting that growth in large cells is restricted by genome concentration in a manner that mimics a limiting nutrient. Moreover, genome dilution explains some proteomic changes ascribed to yeast aging. Overall, our data indicate that genome concentration drives changes in cell composition independently of external environmental cues.

    View details for DOI 10.1038/s41594-024-01353-z

    View details for PubMedID 39048803

  • Cell Size Contributes to Single-Cell Proteome Variation. Journal of proteome research Lanz, M. C., Fuentes Valenzuela, L., Elias, J. E., Skotheim, J. M. 2023

    Abstract

    Accurate measurements of the molecular composition of single cells will be necessary for understanding the relationship between gene expression and function in diverse cell types. One of the most important phenotypes that differs between cells is their size, which was recently shown to be an important determinant of proteome composition in populations of similarly sized cells. We, therefore, sought to test if the effects of the cell size on protein concentrations were also evident in single-cell proteomics data. Using the relative concentrations of a set of reference proteins to estimate a cell's DNA-to-cell volume ratio, we found that differences in the cell size explain a significant amount of cell-to-cell variance in two published single-cell proteome data sets.

    View details for DOI 10.1021/acs.jproteome.3c00441

    View details for PubMedID 37910793

  • Increasing cell size remodels the proteome and promotes senescence. Molecular cell Lanz, M. C., Zatulovskiy, E., Swaffer, M. P., Zhang, L., Ilerten, I., Zhang, S., You, D. S., Marinov, G., McAlpine, P., Elias, J. E., Skotheim, J. M. 2022

    Abstract

    Cell size is tightly controlled in healthy tissues, but it is unclear how deviations in cell size affect cell physiology. To address this, we measured how the cell's proteome changes with increasing cell size. Size-dependent protein concentration changes are widespread and predicted by subcellular localization, size-dependent mRNA concentrations, and protein turnover. As proliferating cells grow larger, concentration changes typically associated with cellular senescence are increasingly pronounced, suggesting that large size may be a cause rather than just a consequence of cell senescence. Consistent with this hypothesis, larger cells are prone to replicative, DNA-damage-induced, and CDK4/6i-induced senescence. Size-dependent changes to the proteome, including those associated with senescence, are not observed when an increase in cell size is accompanied by an increase in ploidy. Together, our findings show how cell size could impact many aspects of cell physiology by remodeling the proteome and provide a rationale for cell size control and polyploidization.

    View details for DOI 10.1016/j.molcel.2022.07.017

    View details for PubMedID 35987199

  • Whi5 is diluted and protein synthesis does not dramatically increase in pre-Start G1. Molecular biology of the cell Schmoller, K. M., Lanz, M. C., Kim, J., Koivomagi, M., Qu, Y., Tang, C., Kukhtevich, I. V., Schneider, R., Rudolf, F., Moreno, D. F., Aldea, M., Lucena, R., Skotheim, J. M. 2022; 33 (5): lt1

    View details for DOI 10.1091/mbc.E21-01-0029

    View details for PubMedID 35482510

  • Delineation of proteome changes driven by cell size and growth rate. Frontiers in cell and developmental biology Zatulovskiy, E., Lanz, M. C., Zhang, S., McCarthy, F., Elias, J. E., Skotheim, J. M. 2022; 10: 980721

    Abstract

    Increasing cell size drives changes to the proteome, which affects cell physiology. As cell size increases, some proteins become more concentrated while others are diluted. As a result, the state of the cell changes continuously with increasing size. In addition to these proteomic changes, large cells have a lower growth rate (protein synthesis rate per unit volume). That both the cell's proteome and growth rate change with cell size suggests they may be interdependent. To test this, we used quantitative mass spectrometry to measure how the proteome changes in response to the mTOR inhibitor rapamycin, which decreases the cellular growth rate and has only a minimal effect on cell size. We found that large cell size and mTOR inhibition, both of which lower the growth rate of a cell, remodel the proteome in similar ways. This suggests that many of the effects of cell size are mediated by the size-dependent slowdown of the cellular growth rate. For example, the previously reported size-dependent expression of some senescence markers could reflect a cell's declining growth rate rather than its size per se. In contrast, histones and other chromatin components are diluted in large cells independently of the growth rate, likely so that they remain in proportion with the genome. Finally, size-dependent changes to the cell's growth rate and proteome composition are still apparent in cells continually exposed to a saturating dose of rapamycin, which indicates that cell size can affect the proteome independently of mTORC1 signaling. Taken together, our results clarify the dependencies between cell size, growth, mTOR activity, and the proteome remodeling that ultimately controls many aspects of cell physiology.

    View details for DOI 10.3389/fcell.2022.980721

    View details for PubMedID 36133920

  • In-depth and 3-dimensional exploration of the budding yeast phosphoproteome EMBO REPORTS Lanz, M. C., Yugandhar, K., Gupta, S., Sanford, E. J., Faca, V. M., Vega, S., Joiner, A. M. N., Fromme, J., Yu, H., Smolka, M. B. 2021: e51121

    Abstract

    Phosphorylation is one of the most dynamic and widespread post-translational modifications regulating virtually every aspect of eukaryotic cell biology. Here, we assemble a dataset from 75 independent phosphoproteomic experiments performed in our laboratory using Saccharomyces cerevisiae. We report 30,902 phosphosites identified from cells cultured in a range of DNA damage conditions and/or arrested in distinct cell cycle stages. To generate a comprehensive resource for the budding yeast community, we aggregate our dataset with the Saccharomyces Genome Database and another recently published study, resulting in over 46,000 budding yeast phosphosites. With the goal of enhancing the identification of functional phosphorylation events, we perform computational positioning of phosphorylation sites on available 3D protein structures and systematically identify events predicted to regulate protein complex architecture. Results reveal hundreds of phosphorylation sites mapping to or near protein interaction interfaces, many of which result in steric or electrostatic "clashes" predicted to disrupt the interaction. With the advancement of Cryo-EM and the increasing number of available structures, our approach should help drive the functional and spatial exploration of the phosphoproteome.

    View details for DOI 10.15252/embr.202051121

    View details for Web of Science ID 000610988800001

    View details for PubMedID 33491328

    View details for PubMedCentralID PMC7857435