Molecular Cell最新文献_第8页

Hypertranscription caused by p53 deficiency triggers nucleotide insufficiency that induces replication stress and genomic instability 由p53缺陷引起的超转录触发核苷酸不足，诱导复制应激和基因组不稳定

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-03 DOI: 10.1016/j.molcel.2026.08.003

Wisam Zaatra,George Philippos,Petr Smirnov,Shira Milo,Jan Otoničar,Michelle Chan,Michal Harel,Frauke Devens,Tchelet Goldberg,Alexandra Eliassaf,Karen Grimes,Michal Irony-Tur Sinai,Gianluca Sigismondo,Kathrin Laue,Uri Ben-David,Tamar Geiger,Jan O. Korbel,Jeroen Krijgsveld,Ori Shalev,Batsheva Kerem,Aurélie Ernst

{"title":"Hypertranscription caused by p53 deficiency triggers nucleotide insufficiency that induces replication stress and genomic instability","authors":"Wisam Zaatra,George Philippos,Petr Smirnov,Shira Milo,Jan Otoničar,Michelle Chan,Michal Harel,Frauke Devens,Tchelet Goldberg,Alexandra Eliassaf,Karen Grimes,Michal Irony-Tur Sinai,Gianluca Sigismondo,Kathrin Laue,Uri Ben-David,Tamar Geiger,Jan O. Korbel,Jeroen Krijgsveld,Ori Shalev,Batsheva Kerem,Aurélie Ernst","doi":"10.1016/j.molcel.2026.08.003","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.003","url":null,"abstract":"p53 plays a central role in the DNA damage response, inducing repair, cell-cycle arrest or apoptosis. Its loss is associated with replication stress and genomic instability. While several underlying mechanisms were suggested, the primary triggers of catastrophic genomic events like chromothripsis, a known driver of tumorigenesis linked with p53 loss, are still unclear. Using p53-depleted epithelial cells and fibroblasts, as well as patient-derived fibroblasts with germline p53 variants that spontaneously undergo chromothripsis, we found that p53 loss causes hypertranscription and increased nucleotide consumption. The resulting nucleotide shortage induces replication stress, causing telomere dysfunction, micronuclei formation, and chromothripsis. These effects were rescued by nucleoside supplementation or normalization of transcription levels, demonstrating a causal link between transcriptional activity, nucleotide availability, and genome stability. Emerging chromothriptic clones displayed restored DNA replication, telomere stabilization, and extrachromosomal DNA, suggesting key features that support clonal selection. We identify nucleotide pool homeostasis as a critical p53 function that suppresses replication stress, prevents chromothripsis, and protects against early tumorigenesis.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"43 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877362","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

Hot and Sp(l)icy phosphatase: A potential thermosensor in mammals 热磷酸酶和Sp(1)冰磷酸酶：哺乳动物中一种潜在的热传感器

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-03 DOI: 10.1016/j.molcel.2026.08.009

Márton Szabó,Ritwick Sawarkar

引用次数: 0

To fuse, or not to fuse: Closing in on the nuclear envelope fusion machinery 熔合，还是不熔合：靠近核膜的熔合机器

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-03 DOI: 10.1016/j.molcel.2026.08.012

Dylan Poch,Christian Schlieker

引用次数: 0

BRD4: From molecular understanding to therapeutics development. BRD4：从分子认识到治疗发展。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-03 Epub Date: 2026-07-23 DOI: 10.1016/j.molcel.2026.07.004

Shwu-Yuan Wu, Cheng-Ming Chiang

{"title":"BRD4: From molecular understanding to therapeutics development.","authors":"Shwu-Yuan Wu, Cheng-Ming Chiang","doi":"10.1016/j.molcel.2026.07.004","DOIUrl":"10.1016/j.molcel.2026.07.004","url":null,"abstract":"Bromodomain-containing protein 4 (BRD4) is an important therapeutic target for anticancer, antiviral, and anti-inflammatory responses. Although its role in transcription, chromatin dynamics, and epigenetic programs is well recognized, recent studies have expanded the functions of BRD4 and its related bromodomain and extra-terminal (BET) family members (BRD2, BRD3, and BRDT) to other molecular and biological processes. How a universal epigenetic regulator is tailored for context-specific gene/pathway regulation is mechanistically intriguing. In this review, we highlight the importance of protein isoforms and posttranslational modifications, particularly phosphorylation, in generating the protein diversity necessary for selective factor recruitment and context-dependent regulation. Three BRD4 protein isoforms have been identified, including the universally expressed BRD4-L and BRD4-S(a) (simplified as BRD4-S), representing the long and short isoform a, and cell-/stress-specific short isoform b, BRD4-S(b). A phospho-switch mechanism controlling the open/closed state of the bromodomain and BRD4 interaction with partner proteins will also be discussed. Mechanistic understanding of BET protein action has led not only to the development of diverse bromodomain-binding compounds currently used in clinical trials but also to the discovery of a new class of small-molecule inhibitors targeting an intrinsically disordered region (IDR) of phospho-BRD4 to alter specific protein-protein interaction (PPI) networks without globally perturbing transcription programs and chromatin landscapes, thus significantly reducing off-target effects and providing new directions for therapeutic drug development.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3367-3393"},"PeriodicalIF":16.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13430956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579488","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

Ac4C adds a new letter to the mRNA medicine lexicon Ac4C为mRNA医学词典增加了一个新字母

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-03 DOI: 10.1016/j.molcel.2026.08.011

Kristin S. Koutmou

引用次数: 0

A conserved mechanism of membrane fusion in nuclear pore complex assembly. 核孔复合物组装中膜融合的保守机制。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-03 Epub Date: 2026-07-09 DOI: 10.1016/j.molcel.2026.06.023

Jonas S Fischer, Matthias Wojtynek, Ashutosh Kumar, Harry Baird, Kateřina Radilová, Daria Maslennikova, Kaustubh Ramachandran, Anna N Becker, Arantxa Agote-Aran, Alessia Loffreda, Annemarie Kralt, Madhav Jagannathan, Gautam Dey, Ulrike Kutay, Stefano Vanni, Karsten Weis

{"title":"A conserved mechanism of membrane fusion in nuclear pore complex assembly.","authors":"Jonas S Fischer, Matthias Wojtynek, Ashutosh Kumar, Harry Baird, Kateřina Radilová, Daria Maslennikova, Kaustubh Ramachandran, Anna N Becker, Arantxa Agote-Aran, Alessia Loffreda, Annemarie Kralt, Madhav Jagannathan, Gautam Dey, Ulrike Kutay, Stefano Vanni, Karsten Weis","doi":"10.1016/j.molcel.2026.06.023","DOIUrl":"10.1016/j.molcel.2026.06.023","url":null,"abstract":"The nuclear pore complex (NPC) serves as the central transport gateway between nucleus and cytoplasm. NPC biogenesis requires the assembly of over 500 proteins culminating in the fusion of the inner and outer nuclear membranes. The mechanism of membrane fusion is unknown. Here, we elucidate how Brl1 and Brr6 mediate membrane fusion in S. cerevisiae. Our data suggest that both proteins form ring-shaped complexes with membrane-remodeling activity. Brl1 localizes to NPC assembly sites via a nuclear export sequence and interacts with Brr6 across the nuclear envelope through conserved hydrophobic loops. Disrupting this interaction blocks fusion and halts NPC assembly. Molecular dynamics simulations suggest that the Brl1-Brr6 complex drives membrane fusion by forming a channel across the bilayers enabling lipid exchange. Phylogenetic analyses and functional experiments in human cells and D. melanogaster establish CLCC1 as the NPC fusogen in metazoans. Together, our results uncover a conserved membrane fusion mechanism in eukaryotes.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3482-3497.e8"},"PeriodicalIF":16.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422727","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

Cyclin E-CDK2 regulates cancer cell transcriptional program and response to immunotherapy through BRD4 Cyclin E-CDK2通过BRD4调控癌细胞转录程序和免疫治疗反应

IF 16 1区生物学

Molecular Cell Pub Date : 2026-09-02 DOI: 10.1016/j.molcel.2026.08.007

Chen Chu,Shanshan Zheng,Ning Mitchell,Zheqi Li,Xixi Zhang,Xiaowei Wu,Tian Zhang,Fabin Dang,Wojciech Michowski,Aleksandra Kolodziejczyk,Miranda L. Xu,Krzysztof W. Kotowski,Zhe Yang,Diego Martinez-Alonso,Joao Paulo,Jindan Sheng,Jane A. Kirby,Finn Groezinger,Yubin Zhou,Miao He,Yoshinaga Ito,Anushree C. Gulvady,Michael I. Cole,Pierre Foidart,Jun Nishida,Xiaohan Ning,Samanta Sharma,Jan M. Suski,Anne Fassl,Yu Zhou,Yan Geng,Wenyi Wei,Steven P. Gygi,Kornelia Polyak,Kai W. Wucherpfennig,Piotr Sicinski

{"title":"Cyclin E-CDK2 regulates cancer cell transcriptional program and response to immunotherapy through BRD4","authors":"Chen Chu,Shanshan Zheng,Ning Mitchell,Zheqi Li,Xixi Zhang,Xiaowei Wu,Tian Zhang,Fabin Dang,Wojciech Michowski,Aleksandra Kolodziejczyk,Miranda L. Xu,Krzysztof W. Kotowski,Zhe Yang,Diego Martinez-Alonso,Joao Paulo,Jindan Sheng,Jane A. Kirby,Finn Groezinger,Yubin Zhou,Miao He,Yoshinaga Ito,Anushree C. Gulvady,Michael I. Cole,Pierre Foidart,Jun Nishida,Xiaohan Ning,Samanta Sharma,Jan M. Suski,Anne Fassl,Yu Zhou,Yan Geng,Wenyi Wei,Steven P. Gygi,Kornelia Polyak,Kai W. Wucherpfennig,Piotr Sicinski","doi":"10.1016/j.molcel.2026.08.007","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.007","url":null,"abstract":"The cyclin E-cyclin-dependent kinase 2 (CDK2) complex is a component of mammalian cell-cycle machinery that drives cell division. Hyperactivation of cyclin E-CDK2 is frequent in human cancers. Small-molecule CDK2 inhibitors are tested in clinical trials for cancer patients. Here, we report that cyclin E-CDK2 has a cell-cycle-independent function in regulating the global transcriptional program of cancer cells. CDK2 phosphorylates bromodomain-containing protein-4 (BRD4) and regulates its chromatin association. Overexpression of cyclin E and the resulting activation of CDK2 in cancer cells alter the cancer cell transcriptome, repress the expression of interferon-stimulated genes, and confer resistance to immunotherapy. Conversely, CDK2 inhibition has the opposite effect and augments the efficacy of immune checkpoint blockade. CDK2 inhibition also increases tumor infiltration by dendritic cells (DCs) and enhances antigen cross-presentation to CD8 T cells. These studies reveal an additional function of cyclin E-CDK2 in tumorigenesis and identify inhibition of CDK2 with clinically available compounds as a strategy for enhancing immune checkpoint blockade.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"27 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877366","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

Promiscuous RNA binding by WDR5 remodels the KMT2A (MLL1) histone methyltransferase complex to an inactive state WDR5的混杂RNA结合将KMT2A （MLL1）组蛋白甲基转移酶复合物重塑为非活性状态

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-31 DOI: 10.1016/j.molcel.2026.08.008

Amoldeep S. Kainth,Pallavi Sirjoosingh,Michael S. Werner,Ankit Gupta,Akiko Koide,Shohei Koide,Alexander J. Ruthenburg

{"title":"Promiscuous RNA binding by WDR5 remodels the KMT2A (MLL1) histone methyltransferase complex to an inactive state","authors":"Amoldeep S. Kainth,Pallavi Sirjoosingh,Michael S. Werner,Ankit Gupta,Akiko Koide,Shohei Koide,Alexander J. Ruthenburg","doi":"10.1016/j.molcel.2026.08.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.008","url":null,"abstract":"Chromatin-modifying complexes are critical in gene regulation, yet their proposed interactions with RNA remain poorly understood. Counter to prior models of specific recruitment, we find that WDR5, an essential subunit of the MLL1/KMT2A histone methyltransferase complex, binds RNA promiscuously. Using a stringent approach, we demonstrate that WDR5 directly engages a diverse pool of cellular RNAs, dictated primarily by RNA abundance rather than specific motifs. Equilibrium binding assays show that RNA length, rather than sequence, governs high affinity. WDR5 binds to RNA through multiple surfaces, some of which overlap with MLL1 complex subunit interfaces. Strikingly, we find that RNA binding disrupts the MLL1 complex by competitively displacing WDR5 from these critical protein-protein interactions, leading to a marked inhibition of MLL1 catalytic activity. Further experiments in human cell lines suggest that this disassembly mechanism may operate to homeostatically downregulate MLL1 complex activity, thereby integrating transcriptional activity with chromatin state.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"53 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148858088","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

An IRAK1-snRNA axis activates ATM to promote accurate repair within transcriptionally active chromatin IRAK1-snRNA轴激活ATM以促进转录活性染色质内的准确修复

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-31 DOI: 10.1016/j.molcel.2026.08.006

Chen Nie,Wanchang Liu,Lei Zhang,Sai Ge,Mingyang Ma,Jundi Wang,Zhanzhan Xu,Yingyu Qin,Xiao Albert Zhou,Yang Liu,Weibin Wang,Jiadong Wang

{"title":"An IRAK1-snRNA axis activates ATM to promote accurate repair within transcriptionally active chromatin","authors":"Chen Nie,Wanchang Liu,Lei Zhang,Sai Ge,Mingyang Ma,Jundi Wang,Zhanzhan Xu,Yingyu Qin,Xiao Albert Zhou,Yang Liu,Weibin Wang,Jiadong Wang","doi":"10.1016/j.molcel.2026.08.006","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.08.006","url":null,"abstract":"Genomic integrity in transcriptionally active regions is pivotal for suppressing oncogenic mutations, yet the mechanisms that govern precise homologous recombination (HR) repair within these regions remain elusive. Here, we report that the IRAK1-spliceosome axis operates with small nuclear RNA (snRNA) as a central hub, potently promoting accurate repair at DNA double-strand break (DSB) sites within active chromatin in human cancer cells. Mechanistically, IRAK1 phosphorylates spliceosomal serine/arginine (SR)-rich proteins to recruit snRNA to DSBs, inducing robust condensation of the MRE11-RAD50-NBS1 (MRN) complex near transcriptionally active regions to create an ATM activation platform. Collectively, our findings define a prevalent mechanism governing region-specific precise repair in transcriptionally active domains, where snRNA acts as a “transcription repair bridge” to link transcriptional processes to HR repair and ultimately preserves genomic stability. Inhibiting IRAK1 axis impairs HR repair in transcriptionally active regions, causing a marked increase in mutation rates specific to these regions and cancer-cell chemosensitivity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"42 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148858089","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 single-stranded DNA suppression by DDIAS DDIAS抑制有丝分裂单链DNA

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-24 DOI: 10.1016/j.molcel.2026.07.034

Yibo Xue,Faisal Bin Rashed,Daniel Y.L. Mao,Kento T. Abe,Zhen-Yuan Lin,Dragomir B. Krastev,Dheva Setiaputra,Lisa Hoeg,Clara Bonnet,Arun Kumar,Antranik Mavousian,Arussa Maan,Elizabeth Harvey-Jones,Stephen J. Pettitt,Andrew N.J. Tutt,Christopher J. Lord,Frank Sicheri,Anne-Claude Gingras,Daniel Durocher

{"title":"Mitotic single-stranded DNA suppression by DDIAS","authors":"Yibo Xue,Faisal Bin Rashed,Daniel Y.L. Mao,Kento T. Abe,Zhen-Yuan Lin,Dragomir B. Krastev,Dheva Setiaputra,Lisa Hoeg,Clara Bonnet,Arun Kumar,Antranik Mavousian,Arussa Maan,Elizabeth Harvey-Jones,Stephen J. Pettitt,Andrew N.J. Tutt,Christopher J. Lord,Frank Sicheri,Anne-Claude Gingras,Daniel Durocher","doi":"10.1016/j.molcel.2026.07.034","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.07.034","url":null,"abstract":"Cells undergoing division mount a unique response to DNA damage that ensures accurate chromosome segregation. The CIP2A-TOPBP1 complex has emerged as an important mitotic genome maintenance factor, but its function remains unclear. Here, we report that DDIAS is a DNA-binding effector of the CIP2A pathway in human cells. DDIAS physically interacts with TOPBP1, and its inactivation causes synthetic lethality with BRCA1 and BRCA2 deficiency. Homologous recombination (HR)-deficient tumors upregulate DDIAS to enable HR-deficient cells to tolerate their genomic instability. Mechanistically, DDIAS is a single-stranded DNA (ssDNA)-binding protein that promotes the repair of ssDNA carried from interphase into mitosis. Mitotic ssDNA in HR-deficient cells is exacerbated by poly(ADP-ribose) polymerase (PARP) inhibition, and DDIAS-dependent suppression of these lesions involves mitotic DNA synthesis, which promotes accurate chromosome segregation and survival. We propose that DDIAS defines a mitotic DNA repair system downstream of CIP2A that mitigates the threat of mitotic ssDNA for genome integrity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"6 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148806408","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