Molecular Cell最新文献_第10页

YTHDC1 cooperates with the THO complex to prevent RNA-damage-induced DNA breaks YTHDC1与THO复合物协同防止rna损伤诱导的DNA断裂

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-03 DOI: 10.1016/j.molcel.2025.02.003

Ning Tsao, Patrick M. Lombardi, Ajin Park, Jennifer Olabode, Rebecca Rodell, Hua Sun, Shilpa Padmanaban, Joshua R. Brickner, Miaw-Sheue Tsai, Elizabeth A. Pollina, Chun-Kan Chen, Nima Mosammaparast

{"title":"YTHDC1 cooperates with the THO complex to prevent RNA-damage-induced DNA breaks","authors":"Ning Tsao, Patrick M. Lombardi, Ajin Park, Jennifer Olabode, Rebecca Rodell, Hua Sun, Shilpa Padmanaban, Joshua R. Brickner, Miaw-Sheue Tsai, Elizabeth A. Pollina, Chun-Kan Chen, Nima Mosammaparast","doi":"10.1016/j.molcel.2025.02.003","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.02.003","url":null,"abstract":"Certain environmental toxins and chemotherapeutics are nucleic acid-damaging agents, causing adducts in DNA and RNA. While most of these adducts occur in RNA, the consequences of RNA damage are largely unexplored. Here, we demonstrate that nuclear RNA damage can result in loss of genome integrity in human cells. Specifically, we show that YTHDC1 regulates alkylation damage responses with the THO complex (THOC). In addition to its established binding to N6-methyladenosine (m6A), YTHDC1 binds to chemically induced N1-methyladenosine (m1A). Without YTHDC1, cells have greater alkylation damage sensitivity and increased DNA breaks, which are rescued by an RNA-specific dealkylase. These RNA-damage-induced DNA breaks (RDIBs) depend on R-loop formation, which is converted to DNA breaks by the XPG nuclease. Strikingly, in the absence of YTHDC1 or THOC, a nuclear RNA m1A methyltransferase is sufficient to induce DNA breaks. Our results provide mechanistic insight into how damaged RNAs can impact genomic integrity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"84 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532351","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

Pcf11/Spt5 condensates stall RNA polymerase II to facilitate termination and piRNA-guided heterochromatin formation Pcf11/Spt5凝聚阻滞RNA聚合酶II，促进终止和pirna引导的异染色质形成

IF 16 1区生物学

Molecular Cell Pub Date : 2025-02-26 DOI: 10.1016/j.molcel.2025.01.023

Weiwei Liu, Lijun Deng, Ming Wang, Xiaojun Liu, Xuan Ouyang, Yuan Wang, Na Miao, Xiu Luo, Xueming Wu, Xiaohua Lu, Xiangjin Xv, Tianyu Zhang, Yu Li, Jinyao Ji, Zhenghao Qiao, Sheng Wang, Li Guan, Dong Li, Yunkun Dang, Chao Liu, Yang Yu

{"title":"Pcf11/Spt5 condensates stall RNA polymerase II to facilitate termination and piRNA-guided heterochromatin formation","authors":"Weiwei Liu, Lijun Deng, Ming Wang, Xiaojun Liu, Xuan Ouyang, Yuan Wang, Na Miao, Xiu Luo, Xueming Wu, Xiaohua Lu, Xiangjin Xv, Tianyu Zhang, Yu Li, Jinyao Ji, Zhenghao Qiao, Sheng Wang, Li Guan, Dong Li, Yunkun Dang, Chao Liu, Yang Yu","doi":"10.1016/j.molcel.2025.01.023","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.023","url":null,"abstract":"The PIWI-interacting RNA (piRNA) pathway plays a crucial role in protecting animal germ cells by repressing transposons. However, the mechanism of piRNA-guided heterochromatin formation and its relationship to transcriptional termination remains elusive. Through RNA interference screening, we discovered Pcf11 and PNUTS as essential for piRNA-guided silencing in Drosophila germ line. Enforced tethering of Pcf11 leads to co-transcriptional repression and RNA polymerase II (RNA Pol II) stalling, and both are dependent on an α-helical region of Pcf11 capable of forming condensates. An intrinsically disordered region can substitute for the α-helical region of Pcf11 in its silencing capacity and support animal development, arguing for a causal relationship between phase separation and Pcf11’s function. Pcf11 stalls RNA Pol II by preferentially forming condensates with the unphosphorylated Spt5, promoted by the PP1/PNUTS phosphatase during termination. We propose that Pcf11/Spt5 condensates control termination by decelerating polymerase elongation, a property exploited by piRNAs to silence transposons and initiate RNA-mediated heterochromatin formation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"25 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495770","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

A comprehensive Schizosaccharomyces pombe atlas of physical transcription factor interactions with proteins and chromatin 一个全面的裂糖菌的物理转录因子与蛋白质和染色质相互作用图谱

IF 16 1区生物学

Molecular Cell Pub Date : 2025-02-26 DOI: 10.1016/j.molcel.2025.01.032

Merle Skribbe, Charlotte Soneson, Michael B. Stadler, Michaela Schwaiger, Vishnu N. Suma Sreechakram, Vytautas Iesmantavicius, Daniel Hess, Eliza Pandini Figueiredo Moreno, Sigurd Braun, Jan Seebacher, Sebastien A. Smallwood, Marc Bühler

{"title":"A comprehensive Schizosaccharomyces pombe atlas of physical transcription factor interactions with proteins and chromatin","authors":"Merle Skribbe, Charlotte Soneson, Michael B. Stadler, Michaela Schwaiger, Vishnu N. Suma Sreechakram, Vytautas Iesmantavicius, Daniel Hess, Eliza Pandini Figueiredo Moreno, Sigurd Braun, Jan Seebacher, Sebastien A. Smallwood, Marc Bühler","doi":"10.1016/j.molcel.2025.01.032","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.032","url":null,"abstract":"Transcription factors (TFs) are key regulators of gene expression, yet many of their targets and modes of action remain unknown. In Schizosaccharomyces pombe, one-third of TFs are solely homology predicted, with few experimentally validated. We created a comprehensive library of 89 endogenously tagged S. pombe TFs, mapping their protein and chromatin interactions using immunoprecipitation-mass spectrometry and chromatin immunoprecipitation sequencing. Our study identified protein interactors for half the TFs, with over a quarter potentially forming stable complexes. We discovered DNA-binding sites for most TFs across 2,027 unique genomic regions, revealing motifs for 38 TFs and uncovering a complex network of extensive TF cross- and autoregulation. Characterization of the largest TF family revealed conserved DNA sequence preferences but diverse binding patterns and identified a repressive heterodimer, Ntu1/Ntu2, linked to perinuclear gene localization. Our TFexplorer webtool makes all data interactively accessible, offering insights into TF interactions and regulatory mechanisms with broad biological relevance.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"36 1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495772","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

Predictomes, a classifier-curated database of AlphaFold-modeled protein-protein interactions Predictomes，一个分类器管理的alphafold模型蛋白质-蛋白质相互作用数据库

IF 16 1区生物学

Molecular Cell Pub Date : 2025-02-26 DOI: 10.1016/j.molcel.2025.01.034

Ernst W. Schmid, Johannes C. Walter

{"title":"Predictomes, a classifier-curated database of AlphaFold-modeled protein-protein interactions","authors":"Ernst W. Schmid, Johannes C. Walter","doi":"10.1016/j.molcel.2025.01.034","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.034","url":null,"abstract":"Protein-protein interactions (PPIs) are ubiquitous in biology, yet a comprehensive structural characterization of the PPIs underlying cellular processes is lacking. AlphaFold-Multimer (AF-M) has the potential to fill this knowledge gap, but standard AF-M confidence metrics do not reliably separate relevant PPIs from an abundance of false positive predictions. To address this limitation, we used machine learning on curated datasets to train a structure prediction and omics-informed classifier (SPOC) that effectively separates true and false AF-M predictions of PPIs, including in proteome-wide screens. We applied SPOC to an all-by-all matrix of nearly 300 human genome maintenance proteins, generating ∼40,000 predictions that can be viewed at predictomes.org<svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg>, where users can also score their own predictions with SPOC. High-confidence PPIs discovered using our approach enable hypothesis generation in genome maintenance. Our results provide a framework for interpreting large-scale AF-M screens and help lay the foundation for a proteome-wide structural interactome.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"68 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495768","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

Architecture remodeling activates the HerA-DUF anti-phage defense system 建筑重塑激活了HerA-DUF抗噬菌体防御系统

IF 16 1区生物学

Molecular Cell Pub Date : 2025-02-25 DOI: 10.1016/j.molcel.2025.02.001

Anthony D. Rish, Elizabeth Fosuah, Zhangfei Shen, Ila A. Marathe, Vicki H. Wysocki, Tian-Min Fu

引用次数: 0

DUF4297 and HerA form abortosome to mediate bacterial immunity against phage infection DUF4297和HerA形成流产体介导噬菌体感染的细菌免疫

IF 16 1区生物学

Molecular Cell Pub Date : 2025-02-25 DOI: 10.1016/j.molcel.2024.12.010

Dongmei Tang, Ting Liu, Yijun Chen, Zixuan Zhu, Hao Chen, Qiang Chen, Yamei Yu

{"title":"DUF4297 and HerA form abortosome to mediate bacterial immunity against phage infection","authors":"Dongmei Tang, Ting Liu, Yijun Chen, Zixuan Zhu, Hao Chen, Qiang Chen, Yamei Yu","doi":"10.1016/j.molcel.2024.12.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.010","url":null,"abstract":"Immune receptors form higher-order complexes known as inflammasomes in animals and resistosomes in plants to mediate immune signaling. Here, we report a similar bacterial protein complex, DUF4297-HerA, which induces abortive infection to mediate anti-phage immunity by coupling nuclease and ATPase activities. Therefore, we name this defense system “Hailibu” after a hunter in a popular folk tale who sacrifices himself to save his village. Cryoelectron microscopy (cryo-EM) results reveal that DUF4297 and HerA assemble into a higher-order complex, reminiscent of apoptosome, inflammasome, or resistosome, which we refer to as an abortosome. By capturing cryo-EM structures of the pre-loading, DNA-loading, and DNA-transporting states during Hailibu abortosome processing of DNA, we propose that DNA substrates are loaded through the HerA hexamer, with adenosine triphosphate (ATP) hydrolysis providing the energy to transport DNA substrates to the clustered DUF4297 Cap4 nuclease domains for degradation. This study demonstrates the existence of analogous multiprotein complexes in innate immunity across the kingdoms of life.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"119 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486525","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

Uracil processing by SMUG1 in the absence of UNG triggers homologous recombination and selectively kills BRCA1/2-deficient tumors 在没有UNG的情况下，SMUG1加工尿嘧啶触发同源重组并选择性地杀死brca1 /2缺陷肿瘤

IF 16 1区生物学

Molecular Cell Pub Date : 2025-02-25 DOI: 10.1016/j.molcel.2025.01.031

Daniele Musiani, Hatice Yücel, Marie Vallette, Annapaola Angrisani, Rania El Botty, Bérengère Ouine, Niccolo Schintu, Caroline Adams, Manon Chevalier, Derrien Heloise, Ahmed El Marjou, Ivan Nemazanyy, Marie Regairaz, Elisabetta Marangoni, Daniele Fachinetti, Raphael Ceccaldi

{"title":"Uracil processing by SMUG1 in the absence of UNG triggers homologous recombination and selectively kills BRCA1/2-deficient tumors","authors":"Daniele Musiani, Hatice Yücel, Marie Vallette, Annapaola Angrisani, Rania El Botty, Bérengère Ouine, Niccolo Schintu, Caroline Adams, Manon Chevalier, Derrien Heloise, Ahmed El Marjou, Ivan Nemazanyy, Marie Regairaz, Elisabetta Marangoni, Daniele Fachinetti, Raphael Ceccaldi","doi":"10.1016/j.molcel.2025.01.031","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.031","url":null,"abstract":"Resistance to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) is the major obstacle to their effectiveness in the treatment of homologous recombination (HR)-deficient (HRD) tumors. Hence, developing alternative treatments for HRD tumors is critical. Here, we show that targeting the uracil excision pathway kills HRD tumors, including those with PARPi resistance. We found that the interplay between the two major uracil DNA glycosylases UNG and SMUG1 is regulated by nuclear nicotinamide adenine dinucleotide (NAD+), which maintains UNG at replication forks (RFs) and restrains SMUG1 chromatin binding. In the absence of UNG, SMUG1 retention on chromatin leads to persistent abasic sites, which incision by APE1 results in PARP1 hyperactivation, stalled RFs, and RAD51 foci. In HRD cells (i.e., BRCA1/2-deficient), this leads to under-replicated DNA that, when propagated throughout mitosis, results in chromosome fragmentation and cell death. Our findings open up unique possibilities for targeted therapies for HRD tumors based on UNG inhibition and uracil accumulation in the genome.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"15 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486502","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

tRNA intron-derived small regulatory RNAs fine-tune gene expression under oxidative stress tRNA内含子衍生的小调控rna在氧化应激下微调基因表达

IF 16 1区生物学

Molecular Cell Pub Date : 2025-02-20 DOI: 10.1016/j.molcel.2025.01.026

Duo Pan, Mo-Fang Liu

引用次数: 0

Moving epigenetic inheritance into the space age: Evidence that 3D genome organization is required for the establishment of epigenetic memory 将表观遗传带入太空时代：三维基因组组织是建立表观遗传记忆所必需的证据

IF 16 1区生物学

Molecular Cell Pub Date : 2025-02-20 DOI: 10.1016/j.molcel.2025.01.033

Jessica J. Hawes, Alyson Ashe

引用次数: 0

COMET enables direct screening for interactions between E3 ubiquitin ligases and their proteolytic target proteins COMET能够直接筛选E3泛素连接酶与其蛋白水解靶蛋白之间的相互作用