Stephen M. Hinshaw

All Publications

• Convergence of coronary artery disease genes onto endothelial cell programs. Nature Schnitzler, G. R., Kang, H., Fang, S., Angom, R. S., Lee-Kim, V. S., Ma, X. R., Zhou, R., Zeng, T., Guo, K., Taylor, M. S., Vellarikkal, S. K., Barry, A. E., Sias-Garcia, O., Bloemendal, A., Munson, G., Guckelberger, P., Nguyen, T. H., Bergman, D. T., Hinshaw, S., Cheng, N., Cleary, B., Aragam, K., Lander, E. S., Finucane, H. K., Mukhopadhyay, D., Gupta, R. M., Engreitz, J. M. 2024

  Abstract

  Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1-3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1-6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.

  View details for DOI 10.1038/s41586-024-07022-x

  View details for PubMedID 38326615

  View details for PubMedCentralID 5501872

• Recognition of centromere-specific histone Cse4 by the inner kinetochore Okp1-Ame1 complex. EMBO reports Deng, S., Cai, J., Harrison, S. C., Zhou, H., Hinshaw, S. M. 2023: e57702

  Abstract

  Successful mitosis depends on the timely establishment of correct chromosomal attachments to microtubules. The kinetochore, a modular multiprotein complex, mediates this connection by recognizing specialized chromatin containing a histone H3 variant called Cse4 in budding yeast and CENP-A in vertebrates. Structural features of the kinetochore that enable discrimination between Cse4/CENP-A and H3 have been identified in several species. How and when these contribute to centromere recognition and how they relate to the overall structure of the inner kinetochore are unsettled questions. More generally, this molecular recognition ensures that only one kinetochore is built on each chromatid and that this happens at the right place on the chromatin fiber. We have determined the crystal structure of a Cse4 peptide bound to the essential inner kinetochore Okp1-Ame1 heterodimer from budding yeast. The structure and related experiments show in detail an essential point of Cse4 contact and provide information about the arrangement of the inner kinetochore.

  View details for DOI 10.15252/embr.202357702

  View details for PubMedID 37983946

• Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry. Journal of the American Chemical Society Sarott, R. C., You, I., Li, Y. D., Toenjes, S. T., Donovan, K. A., Seo, P., Ordonez, M., Byun, W. S., Hassan, M. M., Wachter, F., Chouchani, E. T., Słabicki, M., Fischer, E. S., Ebert, B. L., Hinshaw, S. M., Gray, N. S. 2023

  Abstract

  Targeted protein degradation relies on small molecules that induce new protein-protein interactions between targets and the cellular protein degradation machinery. Most of these small molecules feature specific ligands for ubiquitin ligases. Recently, the attachment of cysteine-reactive chemical groups to pre-existing small molecule inhibitors has been shown to drive specific target degradation. We demonstrate here that different cysteine-reactive groups can specify target degradation via distinct ubiquitin ligases. By focusing on the bromodomain ligand JQ1, we identify cysteine-reactive functional groups that drive BRD4 degradation by either DCAF16 or DCAF11. Unlike proteolysis-targeting chimeric molecules (PROTACs), the new compounds use a single small molecule ligand with a well-positioned cysteine-reactive group to induce protein degradation. The finding that nearly identical compounds can engage multiple ubiquitination pathways suggests that targeting cellular pathways that search for and eliminate chemically reactive proteins is a feasible avenue for converting existing small molecule drugs into protein degrader molecules.

  View details for DOI 10.1021/jacs.3c06622

  View details for PubMedID 37767920

• Targeted kinase degradation via the KLHDC2 ubiquitin E3 ligase. Cell chemical biology Kim, Y., Seo, P., Jeon, E., You, I., Hwang, K., Kim, N., Tse, J., Bae, J., Choi, H., Hinshaw, S. M., Gray, N. S., Sim, T. 2023

  Abstract

  Chemically induced protein degradation is a powerful strategy for perturbing cellular biochemistry. The predominant mechanism of action for protein degrader drugs involves an induced proximity between the cellular ubiquitin-conjugation machinery and a target. Unlike traditional small molecule enzyme inhibition, targeted protein degradation can clear an undesired protein from cells. We demonstrate here the use of peptide ligands for Kelch-like homology domain-containing protein 2 (KLHDC2), a substrate adapter protein and member of the cullin-2 (CUL2) ubiquitin ligase complex, for targeted protein degradation. Peptide-based bivalent compounds that can induce proximity between KLHDC2 and target proteins cause degradation of the targeted factors. The cellular activity of these compounds depends on KLHDC2 binding. This work demonstrates the utility of KLHDC2 for targeted protein degradation and exemplifies a strategy for the rational design of peptide-based ligands useful for this purpose.

  View details for DOI 10.1016/j.chembiol.2023.07.008

  View details for PubMedID 37567174

• Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors. Journal of medicinal chemistry Lu, W., Fan, M., Ji, W., Tse, J., You, I., Ficarro, S. B., Tavares, I., Che, J., Kim, A. Y., Zhu, X., Boghossian, A., Rees, M. G., Ronan, M. M., Roth, J. A., Hinshaw, S. M., Nabet, B., Corsello, S. M., Kwiatkowski, N., Marto, J. A., Zhang, T., Gray, N. S. 2023

  Abstract

  Transcriptional enhanced associate domain (TEAD) proteins together with their transcriptional coactivator yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) are important transcription factors and cofactors that regulate gene expression in the Hippo pathway. In mammals, the TEAD families have four homologues: TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), and TEAD4 (TEF-3). Aberrant expression and hyperactivation of TEAD/YAP signaling have been implicated in a variety of malignancies. Recently, TEADs were recognized as being palmitoylated in cells, and the lipophilic palmitate pocket has been successfully targeted by both covalent and noncovalent ligands. In this report, we present the medicinal chemistry effort to develop MYF-03-176 (compound 22) as a selective, cysteine-covalent TEAD inhibitor. MYF-03-176 (compound 22) significantly inhibits TEAD-regulated gene expression and proliferation of the cell lines with TEAD dependence including those derived from mesothelioma and liposarcoma.

  View details for DOI 10.1021/acs.jmedchem.2c01548

  View details for PubMedID 36946421

• Lactate regulates cell cycle by remodeling the anaphase promoting complex. Nature Liu, W., Wang, Y., Bozi, L. H., Fischer, P., Jedrychowski, M. P., Xiao, H., Wu, T., Darabedian, N., He, X., Mills, E. L., Burger, N., Shin, S., Reddy, A., Sprenger, H. G., Tran, N., Winther, S., Hinshaw, S. M., Shen, J., Seo, H. S., Song, K., Xu, A. Z., Sebastian, L., Zhao, J., Dhe-Paganon, S., Che, J., Gygi, S. P., Arthanari, H., Chouchani, E. T. 2023

  Abstract

  Lactate is abundant in rapidly dividing cells due to the requirement for elevated glucose catabolism to support proliferation1-6. However, it is not known whether accumulated lactate affects the proliferative state. Here, we deploy a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we elucidate a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodeling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We discover that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. The above mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient replete growth phase to stimulate timed opening of APC/C, cell division, and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodeling and can overcome anti-mitotic pharmacology via mitotic slippage. Taken together, we define a biochemical mechanism through which lactate directly regulates protein function to control cell cycle and proliferation.

  View details for DOI 10.1038/s41586-023-05939-3

  View details for PubMedID 36921622

• Multi-site phosphorylation of yeast Mif2/CENP-C promotes inner kinetochore assembly. Current biology : CB Hinshaw, S. M., Quan, Y., Cai, J., Zhou, A. L., Zhou, H. 2023

  Abstract

  Kinetochores control eukaryotic chromosome segregation by connecting chromosomal centromeres to spindle microtubules. Duplication of centromeric DNA necessitates kinetochore disassembly and subsequent reassembly on nascent sisters. To search for a regulatory mechanism that controls the earliest steps of this process, we studied Mif2/CENP-C, an essential basal component of the kinetochore. We found that phosphorylation of a central region of Mif2 (Mif2-PEST) enhances inner kinetochore assembly. Eliminating Mif2-PEST phosphorylation sites progressively impairs cellular fitness. The most severe Mif2-PEST mutations are lethal in cells lacking otherwise non-essential inner kinetochore factors. These data show that multi-site phosphorylation of Mif2/CENP-C controls inner kinetochore assembly.

  View details for DOI 10.1016/j.cub.2023.01.012

  View details for PubMedID 36736323

• Recognition of Divergent Viral Substrates by the SARS-CoV-2 Main Protease. ACS infectious diseases MacDonald, E. A., Frey, G., Namchuk, M. N., Harrison, S. C., Hinshaw, S. M., Windsor, I. W. 2021

  Abstract

  The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), is an ideal target for pharmaceutical inhibition. Mpro is conserved among coronaviruses and distinct from human proteases. Viral replication depends on the cleavage of the viral polyprotein at multiple sites. We present crystal structures of SARS-CoV-2 Mpro bound to two viral substrate peptides. The structures show how Mpro recognizes distinct substrates and how subtle changes in substrate accommodation can drive large changes in catalytic efficiency. One peptide, constituting the junction between viral nonstructural proteins 8 and 9 (nsp8/9), has P1' and P2' residues that are unique among the SARS-CoV-2 Mpro cleavage sites but conserved among homologous junctions in coronaviruses. Mpro cleaves nsp8/9 inefficiently, and amino acid substitutions at P1' or P2' can enhance catalysis. Visualization of Mpro with intact substrates provides new templates for antiviral drug design and suggests that the coronavirus lifecycle selects for finely tuned substrate-dependent catalytic parameters.

  View details for DOI 10.1021/acsinfecdis.1c00237

  View details for PubMedID 34437808

• Ctf3/CENP-I provides a docking site for the desumoylase Ulp2 at the kinetochore. The Journal of cell biology Quan, Y., Hinshaw, S. M., Wang, P., Harrison, S. C., Zhou, H. 2021; 220 (8)

  Abstract

  The step-by-step process of chromosome segregation defines the stages of the cell cycle. In eukaryotes, signals controlling these steps converge upon the kinetochore, a multiprotein assembly that connects spindle microtubules to chromosomal centromeres. Kinetochores control and adapt to major chromosomal transactions, including replication of centromeric DNA, biorientation of sister centromeres on the metaphase spindle, and transit of sister chromatids into daughter cells during anaphase. Although the mechanisms that ensure tight microtubule coupling at anaphase are at least partly understood, kinetochore adaptations that support other cell cycle transitions are not. We report here a mechanism that enables regulated control of kinetochore sumoylation. A conserved surface of the Ctf3/CENP-I kinetochore protein provides a binding site for Ulp2, the nuclear enzyme that removes SUMO chains from modified substrates. Ctf3 mutations that disable Ulp2 recruitment cause elevated inner kinetochore sumoylation and defective chromosome segregation. The location of the site within the assembled kinetochore suggests coordination between sumoylation and other cell cycle-regulated processes.

  View details for DOI 10.1083/jcb.202012149

  View details for PubMedID 34081091

• The Structural Basis for Kinetochore Stabilization by Cnn1/CENP-T CURRENT BIOLOGY Hinshaw, S. M., Harrison, S. C. 2020; 30 (17): 3425-+

  Abstract

  Chromosome segregation depends on a regulated connection between spindle microtubules and centromeric DNA. The kinetochore mediates this connection and ensures it persists during anaphase, when sister chromatids must transit into daughter cells uninterrupted. The Ctf19 complex (Ctf19c) forms the centromeric base of the kinetochore in budding yeast. Biochemical experiments show that Ctf19c members associate hierarchically when purified from cell extract [1], an observation that is mostly explained by the structure of the complex [2]. The Ctf3 complex (Ctf3c), which is not required for the assembly of most other Ctf19c factors, disobeys the biochemical assembly hierarchy when observed in dividing cells that lack more basal components [3]. Thus, the biochemical experiments do not completely recapitulate the logic of centromeric Ctf19c assembly. We now present a high-resolution structure of the Ctf3c bound to the Cnn1-Wip1 heterodimer. Associated live-cell imaging experiments provide a mechanism for Ctf3c and Cnn1-Wip1 recruitment to the kinetochore. The mechanism suggests feedback regulation of Ctf19c assembly and unanticipated similarities in kinetochore organization between yeast and vertebrates.

  View details for DOI 10.1016/j.cub.2020.06.024

  View details for Web of Science ID 000569894000004

  View details for PubMedID 32679099

• The structure of the yeast Ctf3 complex ELIFE Hinshaw, S. M., Dates, A. N., Harrison, S. C. 2019; 8

  Abstract

  Kinetochores are the chromosomal attachment points for spindle microtubules. They are also signaling hubs that control major cell cycle transitions and coordinate chromosome folding. Most well-studied eukaryotes rely on a conserved set of factors, which are divided among two loosely-defined groups, for these functions. Outer kinetochore proteins contact microtubules or regulate this contact directly. Inner kinetochore proteins designate the kinetochore assembly site by recognizing a specialized nucleosome containing the H3 variant Cse4/CENP-A. We previously determined the structure, resolved by cryo-electron microscopy (cryo-EM), of the yeast Ctf19 complex (Ctf19c, homologous to the vertebrate CCAN), providing a high-resolution view of inner kinetochore architecture (Hinshaw and Harrison, 2019). We now extend these observations by reporting a near-atomic model of the Ctf3 complex, the outermost Ctf19c sub-assembly seen in our original cryo-EM density. The model is sufficiently well-determined by the new data to enable molecular interpretation of Ctf3 recruitment and function.

  View details for DOI 10.7554/eLife.48215

  View details for Web of Science ID 000518854600001

  View details for PubMedID 31194673

  View details for PubMedCentralID PMC6602579

• The structure of the Ctf19c/CCAN from budding yeast ELIFE Hinshaw, S. M., Harrison, S. C. 2019; 8

  Abstract

  Eukaryotic kinetochores connect spindlemicrotubules to chromosomal centromeres. A group of proteins called the Ctf19 complex (Ctf19c) in yeast and the constitutive centromere associated network (CCAN) in other organisms creates the foundation of a kinetochore. The Ctf19c/CCAN influences the timing of kinetochore assembly, sets its location by associating with a specialized nucleosome containing the histone H3 variant Cse4/CENP-A, and determines the organization of the microtubule attachment apparatus. We present here the structure of a reconstituted 13-subunit Ctf19c determined by cryo-electron microscopy at ~4 Å resolution. The structure accounts for known and inferred contacts with the Cse4 nucleosome and for an observed assembly hierarchy. We describe its implications for establishment of kinetochores and for their regulation by kinases throughout the cell cycle.

  View details for DOI 10.7554/eLife.44239

  View details for Web of Science ID 000460816200001

  View details for PubMedID 30762520

  View details for PubMedCentralID PMC6407923

• Kinetochore Function from the Bottom Up TRENDS IN CELL BIOLOGY Hinshaw, S. M., Harrison, S. C. 2018; 28 (1): 22–33

  Abstract

  During a single human lifetime, nearly one quintillion chromosomes separate from their sisters and transit to their destinations in daughter cells. Unlike DNA replication, chromosome segregation has no template, and, unlike transcription, errors frequently lead to a total loss of cell viability. Rapid progress in recent years has shown how kinetochores enable faithful execution of this process by connecting chromosomal DNA to microtubules. These findings have transformed our idea of kinetochores from cytological features to immense molecular machines and now allow molecular interpretation of many long-appreciated kinetochore functions. In this review we trace kinetochore protein connectivity from chromosomal DNA to microtubules, relating new findings to important points of regulation and function.

  View details for DOI 10.1016/j.tcb.2017.09.002

  View details for Web of Science ID 000418594600004

  View details for PubMedID 28985987

• The Kinetochore Receptor for the Cohesin Loading Complex CELL Hinshaw, S. M., Makrantoni, V., Harrison, S. C., Marston, A. L. 2017; 171 (1): 72-+

  Abstract

  The ring-shaped cohesin complex brings together distant DNA domains to maintain, express, and segregate the genome. Establishing specific chromosomal linkages depends on cohesin recruitment to defined loci. One such locus is the budding yeast centromere, which is a paradigm for targeted cohesin loading. The kinetochore, a multiprotein complex that connects centromeres to microtubules, drives the recruitment of high levels of cohesin to link sister chromatids together. We have exploited this system to determine the mechanism of specific cohesin recruitment. We show that phosphorylation of the Ctf19 kinetochore protein by a conserved kinase, DDK, provides a binding site for the Scc2/4 cohesin loading complex, thereby directing cohesin loading to centromeres. A similar mechanism targets cohesin to chromosomes in vertebrates. These findings represent a complete molecular description of targeted cohesin loading, a phenomenon with wide-ranging importance in chromosome segregation and, in multicellular organisms, transcription regulation.

  View details for DOI 10.1016/j.cell.2017.08.017

  View details for Web of Science ID 000411331800012

  View details for PubMedID 28938124

  View details for PubMedCentralID PMC5610175

• Molecular Structures of Yeast Kinetochore Subcomplexes and Their Roles in Chromosome Segregation Jenni, S., Dimitrova, Y. N., Valverde, R., Hinshaw, S. M., Harrison, S. C., Stewart, D., Stillman, B. COLD SPRING HARBOR LABORATORY PRESS. 2017: 83–89

  Abstract

  Kinetochore molecular architecture exemplifies "form follows function." The simplifications that generated the one-chromosome:one-microtubule linkage in point-centromere yeast have enabled strategies for systematic structural analysis and high-resolution visualization of many kinetochore components, leading to specific proposals for molecular mechanisms. We describe here some structural features that allow a kinetochore to remain attached to the end of a depolymerizing microtubule (MT) and some characteristics of the connections between substructures that permit very sensitive regulation by differential kinase activities. We emphasize in particular the importance of flexible connections between rod-like structural members and the integration of these members into a compliant cage-like assembly anchored on the MT by a sliding molecular ring.

  View details for DOI 10.1101/sqb.2017.82.033738

  View details for Web of Science ID 000484900900008

  View details for PubMedID 29167284

• Structural evidence for Scc4-dependent localization of cohesin loading ELIFE Hinshaw, S. M., Makrantoni, V., Kerr, A., Marston, A. L., Harrison, S. C. 2015; 4: e06057

  Abstract

  The cohesin ring holds newly replicated sister chromatids together until their separation at anaphase. Initiation of sister chromatid cohesion depends on a separate complex, Scc2(NIPBL)/Scc4(Mau2) (Scc2/4), which loads cohesin onto DNA and determines its localization across the genome. Proper cohesin loading is essential for cell division, and partial defects cause chromosome missegregation and aberrant transcriptional regulation, leading to severe developmental defects in multicellular organisms. We present here a crystal structure showing the interaction between Scc2 and Scc4. Scc4 is a TPR array that envelops an extended Scc2 peptide. Using budding yeast, we demonstrate that a conserved patch on the surface of Scc4 is required to recruit Scc2/4 to centromeres and to build pericentromeric cohesion. These findings reveal the role of Scc4 in determining the localization of cohesin loading and establish a molecular basis for Scc2/4 recruitment to centromeres.

  View details for DOI 10.7554/eLife.06057

  View details for Web of Science ID 000356423200001

  View details for PubMedID 26038942

  View details for PubMedCentralID PMC4471937

• The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits Flavivirus Replication ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Carocci, M., Hinshaw, S. M., Rodgers, M. A., Villareal, V. A., Burri, D. J., Pilankatta, R., Maharaj, N. P., Gack, M. U., Stavale, E. J., Warfield, K. L., Yang, P. L. 2015; 59 (1): 85–95

  Abstract

  Dengue virus (DENV), a member of the Flaviviridae family, is a mosquito-borne pathogen and the cause of dengue fever. The increasing prevalence of DENV worldwide heightens the need for an effective vaccine and specific antivirals. Due to the dependence of DENV upon the lipid biosynthetic machinery of the host cell, lipid signaling and metabolism present unique opportunities for inhibiting viral replication. We screened a library of bioactive lipids and modulators of lipid metabolism and identified 4-hydroxyphenyl retinamide (4-HPR) (fenretinide) as an inhibitor of DENV in cell culture. 4-HPR inhibits the steady-state accumulation of viral genomic RNA and reduces viremia when orally administered in a murine model of DENV infection. The molecular target responsible for this antiviral activity is distinct from other known inhibitors of DENV but appears to affect other members of the Flaviviridae, including the West Nile, Modoc, and hepatitis C viruses. Although long-chain ceramides have been implicated in DENV replication, we demonstrate that DENV is insensitive to the perturbation of long-chain ceramides in mammalian cell culture and that the effect of 4-HPR on dihydroceramide homeostasis is separable from its antiviral activity. Likewise, the induction of reactive oxygen species by 4-HPR is not required for the inhibition of DENV. The inhibition of DENV in vivo by 4-HPR, combined with its well-established safety and tolerability in humans, suggests that it may be repurposed as a pan-Flaviviridae antiviral agent. This work also illustrates the utility of bioactive lipid screens for identifying critical interactions of DENV and other viral pathogens with host lipid biosynthesis, metabolism, and signal transduction.

  View details for DOI 10.1128/AAC.04177-14

  View details for Web of Science ID 000348609500010

  View details for PubMedID 25313218

  View details for PubMedCentralID PMC4291433

• An Iml3-Chl4 Heterodimer Links the Core Centromere to Factors Required for Accurate Chromosome Segregation CELL REPORTS Hinshaw, S. M., Harrison, S. C. 2013; 5 (1): 29–36

  Abstract

  Accurate segregation of genetic material in eukaryotes relies on the kinetochore, a multiprotein complex that connects centromeric DNA with microtubules. In yeast and humans, two proteins-Mif2/CENP-C and Chl4/CNEP-N-interact with specialized centromeric nucleosomes and establish distinct but cross-connecting axes of chromatin-microtubule linkage. Proteins recruited by Chl4/CENP-N include a subset that regulates chromosome transmission fidelity. We show that Chl4 and a conserved member of this subset, Iml3, both from Saccharomyces cerevisiae, form a stable protein complex that interacts with Mif2 and Sgo1. We have determined the structures of an Iml3 homodimer and an Iml3-Chl4 heterodimer, which suggest a mechanism for regulating the assembly of this functional axis of the kinetochore. We propose that at the core centromere, the Chl4-Iml3 complex participates in recruiting factors, such as Sgo1, that influence sister chromatid cohesion and encourage sister kinetochore biorientation.

  View details for DOI 10.1016/j.celrep.2013.08.036

  View details for Web of Science ID 000326152100005

  View details for PubMedID 24075991

  View details for PubMedCentralID PMC3888643