Molecular Cell最新文献_第2页

Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates aging in mice. 富精氨酸肽引起的核极应激会引发核糖体病变并加速小鼠衰老。

IF 16 1区生物学

Molecular Cell Pub Date : 2024-04-18 Epub Date: 2024-03-22 DOI: 10.1016/j.molcel.2024.02.031

Oleksandra Sirozh, Anabel Saez-Mas, Bomi Jung, Laura Sanchez-Burgos, Eduardo Zarzuela, Sara Rodrigo-Perez, Ivan Ventoso, Vanesa Lafarga, Oscar Fernandez-Capetillo

{"title":"Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates aging in mice.","authors":"Oleksandra Sirozh, Anabel Saez-Mas, Bomi Jung, Laura Sanchez-Burgos, Eduardo Zarzuela, Sara Rodrigo-Perez, Ivan Ventoso, Vanesa Lafarga, Oscar Fernandez-Capetillo","doi":"10.1016/j.molcel.2024.02.031","DOIUrl":"10.1016/j.molcel.2024.02.031","url":null,"abstract":"Nucleolar stress (NS) has been associated with age-related diseases such as cancer or neurodegeneration. To investigate how NS triggers toxicity, we used (PR)n arginine-rich peptides present in some neurodegenerative diseases as inducers of this perturbation. We here reveal that whereas (PR)n expression leads to a decrease in translation, this occurs concomitant with an accumulation of free ribosomal (r) proteins. Conversely, (PR)n-resistant cells have lower rates of r-protein synthesis, and targeting ribosome biogenesis by mTOR inhibition or MYC depletion alleviates (PR)n toxicity in vitro. In mice, systemic expression of (PR)97 drives widespread NS and accelerated aging, which is alleviated by rapamycin. Notably, the generalized accumulation of orphan r-proteins is a common outcome of chemical or genetic perturbations that induce NS. Together, our study presents a general model to explain how NS induces cellular toxicity and provides in vivo evidence supporting a role for NS as a driver of aging in mammals.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1527-1540.e7"},"PeriodicalIF":16.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape. 转录延伸缺陷将致癌的 SF3B1 突变与染色质景观的靶向改变联系起来。

IF 16 1区生物学

Molecular Cell Pub Date : 2024-04-18 Epub Date: 2024-03-22 DOI: 10.1016/j.molcel.2024.02.032

Prajwal C Boddu, Abhishek K Gupta, Rahul Roy, Bárbara De La Peña Avalos, Anne Olazabal-Herrero, Nils Neuenkirchen, Joshua T Zimmer, Namrata S Chandhok, Darren King, Yasuhito Nannya, Seishi Ogawa, Haifan Lin, Matthew D Simon, Eloise Dray, Gary M Kupfer, Amit Verma, Karla M Neugebauer, Manoj M Pillai

{"title":"Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape.","authors":"Prajwal C Boddu, Abhishek K Gupta, Rahul Roy, Bárbara De La Peña Avalos, Anne Olazabal-Herrero, Nils Neuenkirchen, Joshua T Zimmer, Namrata S Chandhok, Darren King, Yasuhito Nannya, Seishi Ogawa, Haifan Lin, Matthew D Simon, Eloise Dray, Gary M Kupfer, Amit Verma, Karla M Neugebauer, Manoj M Pillai","doi":"10.1016/j.molcel.2024.02.032","DOIUrl":"10.1016/j.molcel.2024.02.032","url":null,"abstract":"Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1. The decreased promoter-proximal RNAPII density reduces both chromatin accessibility and H3K4me3 marks at promoters. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, reverse both transcription and chromatin changes. Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1475-1495.e18"},"PeriodicalIF":16.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A programmable targeted protein-degradation platform for versatile applications in mammalian cells and mice. 可编程靶向蛋白质降解平台，可在哺乳动物细胞和小鼠中进行多种应用。

IF 16 1区生物学

Molecular Cell Pub Date : 2024-04-18 Epub Date: 2024-03-12 DOI: 10.1016/j.molcel.2024.02.019

Xiaoding Ma, Jianli Yin, Longliang Qiao, Hang Wan, Xingwan Liu, Yang Zhou, Jiali Wu, Lingxue Niu, Min Wu, Xinyi Wang, Haifeng Ye

{"title":"A programmable targeted protein-degradation platform for versatile applications in mammalian cells and mice.","authors":"Xiaoding Ma, Jianli Yin, Longliang Qiao, Hang Wan, Xingwan Liu, Yang Zhou, Jiali Wu, Lingxue Niu, Min Wu, Xinyi Wang, Haifeng Ye","doi":"10.1016/j.molcel.2024.02.019","DOIUrl":"10.1016/j.molcel.2024.02.019","url":null,"abstract":"Myriad physiological and pathogenic processes are governed by protein levels and modifications. Controlled protein activity perturbation is essential to studying protein function in cells and animals. Based on Trim-Away technology, we screened for truncation variants of E3 ubiquitinase Trim21 with elevated efficiency (ΔTrim21) and developed multiple ΔTrim21-based targeted protein-degradation systems (ΔTrim-TPD) that can be transfected into host cells. Three ΔTrim-TPD variants are developed to enable chemical and light-triggered programmable activation of TPD in cells and animals. Specifically, we used ΔTrim-TPD for (1) red-light-triggered inhibition of HSV-1 virus proliferation by degrading the packaging protein gD, (2) for chemical-triggered control of the activity of Cas9/dCas9 protein for gene editing, and (3) for blue-light-triggered degradation of two tumor-associated proteins for spatiotemporal inhibition of melanoma tumor growth in mice. Our study demonstrates that multiple ΔTrim21-based controllable TPD systems provide powerful tools for basic biology research and highlight their potential biomedical applications.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1585-1600.e7"},"PeriodicalIF":16.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140120126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mitotic chromosomes are self-entangled and disentangle through a topoisomerase-II-dependent two-stage exit from mitosis. 有丝分裂染色体是自缠结的，并通过依赖拓扑异构酶 II 的两阶段退出有丝分裂而解离。

IF 16 1区生物学

Molecular Cell Pub Date : 2024-04-18 Epub Date: 2024-03-22 DOI: 10.1016/j.molcel.2024.02.025

Erica M Hildebrand, Kirill Polovnikov, Bastiaan Dekker, Yu Liu, Denis L Lafontaine, A Nicole Fox, Ying Li, Sergey V Venev, Leonid A Mirny, Job Dekker

{"title":"Mitotic chromosomes are self-entangled and disentangle through a topoisomerase-II-dependent two-stage exit from mitosis.","authors":"Erica M Hildebrand, Kirill Polovnikov, Bastiaan Dekker, Yu Liu, Denis L Lafontaine, A Nicole Fox, Ying Li, Sergey V Venev, Leonid A Mirny, Job Dekker","doi":"10.1016/j.molcel.2024.02.025","DOIUrl":"10.1016/j.molcel.2024.02.025","url":null,"abstract":"The topological state of chromosomes determines their mechanical properties, dynamics, and function. Recent work indicated that interphase chromosomes are largely free of entanglements. Here, we use Hi-C, polymer simulations, and multi-contact 3C and find that, by contrast, mitotic chromosomes are self-entangled. We explore how a mitotic self-entangled state is converted into an unentangled interphase state during mitotic exit. Most mitotic entanglements are removed during anaphase/telophase, with remaining ones removed during early G1, in a topoisomerase-II-dependent process. Polymer models suggest a two-stage disentanglement pathway: first, decondensation of mitotic chromosomes with remaining condensin loops produces entropic forces that bias topoisomerase II activity toward decatenation. At the second stage, the loops are released, and the formation of new entanglements is prevented by lower topoisomerase II activity, allowing the establishment of unentangled and territorial G1 chromosomes. When mitotic entanglements are not removed in experiments and models, a normal interphase state cannot be acquired.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1422-1441.e14"},"PeriodicalIF":16.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular determinants and signaling effects of PKA RIα phase separation. PKA RIα 相分离的分子决定因素和信号效应

IF 14.5 1区生物学

Molecular Cell Pub Date : 2024-04-18 Epub Date: 2024-03-26 DOI: 10.1016/j.molcel.2024.03.002

Julia C Hardy, Emily H Pool, Jessica G H Bruystens, Xin Zhou, Qingrong Li, Daojia R Zhou, Max Palay, Gerald Tan, Lisa Chen, Jaclyn L C Choi, Ha Neul Lee, Stefan Strack, Dong Wang, Susan S Taylor, Sohum Mehta, Jin Zhang

{"title":"Molecular determinants and signaling effects of PKA RIα phase separation.","authors":"Julia C Hardy, Emily H Pool, Jessica G H Bruystens, Xin Zhou, Qingrong Li, Daojia R Zhou, Max Palay, Gerald Tan, Lisa Chen, Jaclyn L C Choi, Ha Neul Lee, Stefan Strack, Dong Wang, Susan S Taylor, Sohum Mehta, Jin Zhang","doi":"10.1016/j.molcel.2024.03.002","DOIUrl":"10.1016/j.molcel.2024.03.002","url":null,"abstract":"Spatiotemporal regulation of intracellular signaling molecules, such as the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures proper cellular function. Liquid-liquid phase separation (LLPS) of the ubiquitous PKA regulatory subunit RIα promotes cAMP compartmentation and signaling specificity. However, the molecular determinants of RIα LLPS remain unclear. Here, we reveal that two separate dimerization interfaces, combined with the cAMP-induced unleashing of the PKA catalytic subunit (PKA-C) from the pseudosubstrate inhibitory sequence, drive RIα condensate formation in the cytosol of mammalian cells, which is antagonized by docking to A-kinase anchoring proteins. Strikingly, we find that the RIα pseudosubstrate region is critically involved in forming a non-canonical R:C complex, which recruits active PKA-C to RIα condensates to maintain low basal PKA activity in the cytosol. Our results suggest that RIα LLPS not only facilitates cAMP compartmentation but also spatially restrains active PKA-C, thus highlighting the functional versatility of biomolecular condensates in driving signaling specificity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1570-1584.e7"},"PeriodicalIF":14.5,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11031308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The splicing regulators RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites on chromatin. 剪接调节因子 RBM5 和 RBM10 是 U2 snRNP 的亚基，它们与染色质上的内含子分支位点相联系。

IF 16 1区生物学

Molecular Cell Pub Date : 2024-04-18 Epub Date: 2024-03-26 DOI: 10.1016/j.molcel.2024.02.039

Andrey Damianov, Chia-Ho Lin, Jeffrey Huang, Lin Zhou, Yasaman Jami-Alahmadi, Parham Peyda, James Wohlschlegel, Douglas L Black

{"title":"The splicing regulators RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites on chromatin.","authors":"Andrey Damianov, Chia-Ho Lin, Jeffrey Huang, Lin Zhou, Yasaman Jami-Alahmadi, Parham Peyda, James Wohlschlegel, Douglas L Black","doi":"10.1016/j.molcel.2024.02.039","DOIUrl":"10.1016/j.molcel.2024.02.039","url":null,"abstract":"Understanding the mechanisms of pre-mRNA splicing is limited by the technical challenges to examining spliceosomes in vivo. Here, we report the isolation of RNP complexes derived from precatalytic A or B-like spliceosomes solubilized from the chromatin pellet of mammalian cell nuclei. We found that these complexes contain U2 snRNP proteins and a portion of the U2 snRNA bound with protected RNA fragments that precisely map to intronic branch sites across the transcriptome. These U2 complexes also contained the splicing regulators RBM5 and RBM10. We found RBM5 and RBM10 bound to nearly all branch site complexes and not simply those at regulated exons. The deletion of a conserved RBM5/RBM10 peptide sequence, including a zinc finger motif, disrupted U2 interaction and rendered the proteins inactive for the repression of many alternative exons. We propose a model where RBM5 and RBM10 regulate splicing as components of the U2 snRNP complex following branch site base pairing.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1496-1511.e7"},"PeriodicalIF":16.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11057915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Imprinted X chromosome inactivation at the gamete-to-embryo transition. 配子到胚胎转变过程中的X染色体印迹失活。

IF 16 1区生物学

Molecular Cell Pub Date : 2024-04-18 Epub Date: 2024-03-07 DOI: 10.1016/j.molcel.2024.02.013

Chunyao Wei, Barry Kesner, Hao Yin, Jeannie T Lee

{"title":"Imprinted X chromosome inactivation at the gamete-to-embryo transition.","authors":"Chunyao Wei, Barry Kesner, Hao Yin, Jeannie T Lee","doi":"10.1016/j.molcel.2024.02.013","DOIUrl":"10.1016/j.molcel.2024.02.013","url":null,"abstract":"In mammals, dosage compensation involves two parallel processes: (1) X inactivation, which equalizes X chromosome dosage between males and females, and (2) X hyperactivation, which upregulates the active X for X-autosome balance. The field currently favors models whereby dosage compensation initiates \"de novo\" during mouse development. Here, we develop \"So-Smart-seq\" to revisit the question and interrogate a comprehensive transcriptome including noncoding genes and repeats in mice. Intriguingly, de novo silencing pertains only to a subset of Xp genes. Evolutionarily older genes and repetitive elements demonstrate constitutive Xp silencing, adopt distinct signatures, and do not require Xist to initiate silencing. We trace Xp silencing backward in developmental time to meiotic sex chromosome inactivation in the male germ line and observe that Xm hyperactivation is timed to Xp silencing on a gene-by-gene basis. Thus, during the gamete-to-embryo transition, older Xp genes are transmitted in a \"pre-inactivated\" state. These findings have implications for the evolution of imprinting.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1442-1459.e7"},"PeriodicalIF":16.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11031340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A unique chaperoning mechanism in class A JDPs recognizes and stabilizes mutant p53. A 类 JDPs 中的一种独特伴侣机制可识别并稳定突变 p53。

IF 16 1区生物学

Molecular Cell Pub Date : 2024-04-18 Epub Date: 2024-03-19 DOI: 10.1016/j.molcel.2024.02.018

Guy Zoltsman, Thi Lieu Dang, Miriam Kuchersky, Ofrah Faust, Micael S Silva, Tal Ilani, Anne S Wentink, Bernd Bukau, Rina Rosenzweig

{"title":"A unique chaperoning mechanism in class A JDPs recognizes and stabilizes mutant p53.","authors":"Guy Zoltsman, Thi Lieu Dang, Miriam Kuchersky, Ofrah Faust, Micael S Silva, Tal Ilani, Anne S Wentink, Bernd Bukau, Rina Rosenzweig","doi":"10.1016/j.molcel.2024.02.018","DOIUrl":"10.1016/j.molcel.2024.02.018","url":null,"abstract":"J-domain proteins (JDPs) constitute a large family of molecular chaperones that bind a broad spectrum of substrates, targeting them to Hsp70, thus determining the specificity of and activating the entire chaperone functional cycle. The malfunction of JDPs is therefore inextricably linked to myriad human disorders. Here, we uncover a unique mechanism by which chaperones recognize misfolded clients, present in human class A JDPs. Through a newly identified β-hairpin site, these chaperones detect changes in protein dynamics at the initial stages of misfolding, prior to exposure of hydrophobic regions or large structural rearrangements. The JDPs then sequester misfolding-prone proteins into large oligomeric assemblies, protecting them from aggregation. Through this mechanism, class A JDPs bind destabilized p53 mutants, preventing clearance of these oncoproteins by Hsp70-mediated degradation, thus promoting cancer progression. Removal of the β-hairpin abrogates this protective activity while minimally affecting other chaperoning functions. This suggests the class A JDP β-hairpin as a highly specific target for cancer therapeutics.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1512-1526.e9"},"PeriodicalIF":16.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhancer-promoter interactions are reconfigured through the formation of long-range multiway hubs as mouse ES cells exit pluripotency. 当小鼠 ES 细胞退出多能性时，增强子与启动子之间的相互作用通过长程多向中枢的形成而重新配置。

IF 16 1区生物学

Molecular Cell Pub Date : 2024-04-18 Epub Date: 2024-03-14 DOI: 10.1016/j.molcel.2024.02.015

David Lando, Xiaoyan Ma, Yang Cao, Aleksandra Jartseva, Tim J Stevens, Wayne Boucher, Nicola Reynolds, Bertille Montibus, Dominic Hall, Andreas Lackner, Ramy Ragheb, Martin Leeb, Brian D Hendrich, Ernest D Laue

{"title":"Enhancer-promoter interactions are reconfigured through the formation of long-range multiway hubs as mouse ES cells exit pluripotency.","authors":"David Lando, Xiaoyan Ma, Yang Cao, Aleksandra Jartseva, Tim J Stevens, Wayne Boucher, Nicola Reynolds, Bertille Montibus, Dominic Hall, Andreas Lackner, Ramy Ragheb, Martin Leeb, Brian D Hendrich, Ernest D Laue","doi":"10.1016/j.molcel.2024.02.015","DOIUrl":"10.1016/j.molcel.2024.02.015","url":null,"abstract":"Enhancers bind transcription factors, chromatin regulators, and non-coding transcripts to modulate the expression of target genes. Here, we report 3D genome structures of single mouse ES cells as they are induced to exit pluripotency and transition through a formative stage prior to undergoing neuroectodermal differentiation. We find that there is a remarkable reorganization of 3D genome structure where inter-chromosomal intermingling increases dramatically in the formative state. This intermingling is associated with the formation of a large number of multiway hubs that bring together enhancers and promoters with similar chromatin states from typically 5-8 distant chromosomal sites that are often separated by many Mb from each other. In the formative state, genes important for pluripotency exit establish contacts with emerging enhancers within these multiway hubs, suggesting that the structural changes we have observed may play an important role in modulating transcription and establishing new cell identities.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1406-1421.e8"},"PeriodicalIF":16.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140137039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CDK-independent role of D-type cyclins in regulating DNA mismatch repair. D 型细胞周期蛋白在调节 DNA 错配修复中的作用与 CDK 无关。

IF 16 1区生物学

Molecular Cell Pub Date : 2024-04-04 Epub Date: 2024-03-07 DOI: 10.1016/j.molcel.2024.02.010

Gergely Rona, Bearach Miwatani-Minter, Qingyue Zhang, Hailey V Goldberg, Marc A Kerzhnerman, Jesse B Howard, Daniele Simoneschi, Ethan Lane, John W Hobbs, Elizabeth Sassani, Andrew A Wang, Sarah Keegan, Daniel J Laverty, Cortt G Piett, Lorinc S Pongor, Miranda Li Xu, Joshua Andrade, Anish Thomas, Piotr Sicinski, Manor Askenazi, Beatrix Ueberheide, David Fenyö, Zachary D Nagel, Michele Pagano

{"title":"CDK-independent role of D-type cyclins in regulating DNA mismatch repair.","authors":"Gergely Rona, Bearach Miwatani-Minter, Qingyue Zhang, Hailey V Goldberg, Marc A Kerzhnerman, Jesse B Howard, Daniele Simoneschi, Ethan Lane, John W Hobbs, Elizabeth Sassani, Andrew A Wang, Sarah Keegan, Daniel J Laverty, Cortt G Piett, Lorinc S Pongor, Miranda Li Xu, Joshua Andrade, Anish Thomas, Piotr Sicinski, Manor Askenazi, Beatrix Ueberheide, David Fenyö, Zachary D Nagel, Michele Pagano","doi":"10.1016/j.molcel.2024.02.010","DOIUrl":"10.1016/j.molcel.2024.02.010","url":null,"abstract":"Although mismatch repair (MMR) is essential for correcting DNA replication errors, it can also recognize other lesions, such as oxidized bases. In G0 and G1, MMR is kept in check through unknown mechanisms as it is error-prone during these cell cycle phases. We show that in mammalian cells, D-type cyclins are recruited to sites of oxidative DNA damage in a PCNA- and p21-dependent manner. D-type cyclins inhibit the proteasomal degradation of p21, which competes with MMR proteins for binding to PCNA, thereby inhibiting MMR. The ability of D-type cyclins to limit MMR is CDK4- and CDK6-independent and is conserved in G0 and G1. At the G1/S transition, the timely, cullin-RING ubiquitin ligase (CRL)-dependent degradation of D-type cyclins and p21 enables MMR activity to efficiently repair DNA replication errors. Persistent expression of D-type cyclins during S-phase inhibits the binding of MMR proteins to PCNA, increases the mutational burden, and promotes microsatellite instability.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1224-1242.e13"},"PeriodicalIF":16.0,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10997477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0