Molecular Cell最新文献

Putative looping factor ZNF143/ZFP143 is an essential transcriptional regulator with no looping function

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-20 DOI: 10.1016/j.molcel.2024.11.032

Domenic N. Narducci, Anders S. Hansen

引用次数: 0

ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-20 DOI: 10.1016/j.molcel.2024.11.031

Mikhail D. Magnitov, Michela Maresca, Noemí Alonso Saiz, Hans Teunissen, Jinhong Dong, Kizhakke M. Sathyan, Luca Braccioli, Michael J. Guertin, Elzo de Wit

{"title":"ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF","authors":"Mikhail D. Magnitov, Michela Maresca, Noemí Alonso Saiz, Hans Teunissen, Jinhong Dong, Kizhakke M. Sathyan, Luca Braccioli, Michael J. Guertin, Elzo de Wit","doi":"10.1016/j.molcel.2024.11.031","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.031","url":null,"abstract":"Gene expression is orchestrated by transcription factors, which function within the context of a three-dimensional genome. Zinc-finger protein 143 (ZNF143/ZFP143) is a transcription factor that has been implicated in both gene activation and chromatin looping. To study the direct consequences of ZNF143/ZFP143 loss, we generated a ZNF143/ZFP143 depletion system in mouse embryonic stem cells. Our results show that ZNF143/ZFP143 degradation has no effect on chromatin looping. Systematic analysis of ZNF143/ZFP143 occupancy data revealed that a commonly used antibody cross-reacts with CTCF, leading to its incorrect association with chromatin loops. Nevertheless, ZNF143/ZFP143 specifically activates nuclear-encoded mitochondrial genes, and its loss leads to severe mitochondrial dysfunction. Using an in vitro embryo model, we find that ZNF143/ZFP143 is an essential regulator of organismal development. Our results establish ZNF143/ZFP143 as a conserved transcriptional regulator of cell proliferation and differentiation by safeguarding mitochondrial activity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"113 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857798","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

Mutability and hypermutation antagonize immunoglobulin codon optimality

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-20 DOI: 10.1016/j.molcel.2024.11.033

Joshua J.C. McGrath, Juyeon Park, Chloe A. Troxell, Jordan C. Chervin, Lei Li, Johnathan R. Kent, Siriruk Changrob, Yanbin Fu, Min Huang, Nai-Ying Zheng, G. Dewey Wilbanks, Sean A. Nelson, Jiayi Sun, Giorgio Inghirami, Maria Lucia L. Madariaga, George Georgiou, Patrick C. Wilson

{"title":"Mutability and hypermutation antagonize immunoglobulin codon optimality","authors":"Joshua J.C. McGrath, Juyeon Park, Chloe A. Troxell, Jordan C. Chervin, Lei Li, Johnathan R. Kent, Siriruk Changrob, Yanbin Fu, Min Huang, Nai-Ying Zheng, G. Dewey Wilbanks, Sean A. Nelson, Jiayi Sun, Giorgio Inghirami, Maria Lucia L. Madariaga, George Georgiou, Patrick C. Wilson","doi":"10.1016/j.molcel.2024.11.033","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.033","url":null,"abstract":"The efficacy of antibody responses is inherently linked to paratope diversity, as generated through V(D)J recombination and somatic hypermutation. Despite this, it is unclear how genetic diversification mechanisms evolved alongside codon optimality and affect antibody expression. Here, we analyze germline immunoglobulin (IG) genes, natural V(D)J repertoires, serum IgG, and monoclonal antibody (mAb) expression through the lens of codon optimality. Germline variable genes (IGVs) exhibit diverse optimality that is inversely related to mutability. Hypermutation deoptimizes heavy-chain (IGH) VDJ repertoires within human tonsils, bone marrow, lymph nodes (including SARS-CoV-2-specific clones), blood (HIV-1-specific clones), mice, and zebrafish. Analyses of mutation-affected codons show that targeting to complementarity-determining regions constrains deoptimization. Germline IGHV optimality correlates with serum variable fragment (VH) usage after influenza vaccination, while synonymous deoptimization attenuated mAb yield. These findings provide unanticipated insights into an antagonistic relationship between diversification mechanisms and codon optimality. Ultimately, the need for diversity takes precedence over that for the most optimal codon usage.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"10 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857801","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

Dynamic control of RNA-DNA hybrid formation orchestrates DNA2 activation at stalled forks by RNAPII and DDX39A

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-19 DOI: 10.1016/j.molcel.2024.11.034

Lizhi Song, Haihua Xie, Haonan Fan, Yanjun Zhang, Zixiu Cheng, Junliang Chen, Yuzun Guo, Shudi Zhang, Xinyu Zhou, Zhaoshuang Li, Haoxiang Liao, Jinhua Han, Jun Huang, Jianwei Zhou, Dong Fang, Ting Liu

{"title":"Dynamic control of RNA-DNA hybrid formation orchestrates DNA2 activation at stalled forks by RNAPII and DDX39A","authors":"Lizhi Song, Haihua Xie, Haonan Fan, Yanjun Zhang, Zixiu Cheng, Junliang Chen, Yuzun Guo, Shudi Zhang, Xinyu Zhou, Zhaoshuang Li, Haoxiang Liao, Jinhua Han, Jun Huang, Jianwei Zhou, Dong Fang, Ting Liu","doi":"10.1016/j.molcel.2024.11.034","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.034","url":null,"abstract":"Stalled replication forks, susceptible to nucleolytic threats, necessitate protective mechanisms involving pivotal factors such as the tumor suppressors BRCA1 and BRCA2. Here, we demonstrate that, upon replication stress, RNA polymerase II (RNAPII) is recruited to stalled forks, actively promoting the transient formation of RNA-DNA hybrids. These hybrids act as safeguards, preventing premature engagement by the DNA2 nuclease and uncontrolled DNA2-mediated degradation of nascent DNA. Furthermore, we provide evidence that DExD box polypeptide 39A (DDX39A), serving as an RNA-DNA resolver, unwinds these structures and facilitates regulated DNA2 access to stalled forks. This orchestrated process enables controlled DNA2-dependent stalled fork processing and restart. Finally, we reveal that loss of DDX39A enhances stalled fork protection in BRCA1/2-deficient cells, consequently conferring chemoresistance. Our results suggest that the dynamic regulation of RNA-DNA hybrid formation at stalled forks by RNAPII and DDX39A precisely governs the timing of DNA2 activation, contributing to stalled fork protection, processing, and restart, ultimately promoting genome stability.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"25 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849558","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

Keiji Tanaka (1949–2024) 田中圭二（1949-2024）

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-19 DOI: 10.1016/j.molcel.2024.11.020

Shigeo Murata, Kazuhiro Iwai

引用次数: 0

TurboCas: A method for locus-specific labeling of genomic regions and isolating their associated protein interactome

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-19 DOI: 10.1016/j.molcel.2024.11.007

Bercin K. Cenik, Yuki Aoi, Marta Iwanaszko, Benjamin C. Howard, Marc A. Morgan, Grant D. Andersen, Elizabeth T. Bartom, Ali Shilatifard

{"title":"TurboCas: A method for locus-specific labeling of genomic regions and isolating their associated protein interactome","authors":"Bercin K. Cenik, Yuki Aoi, Marta Iwanaszko, Benjamin C. Howard, Marc A. Morgan, Grant D. Andersen, Elizabeth T. Bartom, Ali Shilatifard","doi":"10.1016/j.molcel.2024.11.007","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.007","url":null,"abstract":"Regulation of gene expression during development and stress response requires the concerted action of transcription factors and chromatin-binding proteins. Because this process is cell-type specific and varies with cellular conditions, mapping of chromatin factors at individual regulatory loci is crucial for understanding cis-regulatory control. Previous methods only characterize static protein binding. We present “TurboCas,” a method combining a proximity-labeling (PL) enzyme, miniTurbo, with CRISPR-dCas9 that allows for efficient and site-specific labeling of chromatin factors in mammalian cells. Validating TurboCas at the FOS promoter, we identify proteins recruited upon heat shock, cross-validated via RNA polymerase II and P-TEFb immunoprecipitation. These methodologies reveal canonical and uncharacterized factors that function to activate expression of heat-shock-responsive genes. Applying TurboCas to the MYC promoter, we identify two P-TEFb coactivators, the super elongation complex (SEC) and BRD4, as MYC co-regulators. TurboCas provides a genome-specific targeting PL, with the potential to deepen our molecular understanding of transcriptional regulatory pathways in development and stress response.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"30 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849564","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

DDX39A resolves replication fork-associated RNA-DNA hybrids to balance fork protection and cleavage for genomic stability maintenance

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-19 DOI: 10.1016/j.molcel.2024.11.029

Zhanzhan Xu, Chen Nie, Junwei Liao, Yujie Ma, Xiao Albert Zhou, Xiaoman Li, Shiwei Li, Haodong Lin, Yefei Luo, Kaiqi Cheng, Zuchao Mao, Lei Zhang, Yichen Pan, Yuke Chen, Weibin Wang, Jiadong Wang

{"title":"DDX39A resolves replication fork-associated RNA-DNA hybrids to balance fork protection and cleavage for genomic stability maintenance","authors":"Zhanzhan Xu, Chen Nie, Junwei Liao, Yujie Ma, Xiao Albert Zhou, Xiaoman Li, Shiwei Li, Haodong Lin, Yefei Luo, Kaiqi Cheng, Zuchao Mao, Lei Zhang, Yichen Pan, Yuke Chen, Weibin Wang, Jiadong Wang","doi":"10.1016/j.molcel.2024.11.029","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.029","url":null,"abstract":"Safeguarding replication fork stability in transcriptionally active regions is crucial for precise DNA replication and mutation prevention. Here, we discover the pervasive existence of replication fork-associated RNA-DNA hybrids (RF-RDs) in transcriptionally active regions of human cells. These hybrids function as protective barriers, preventing DNA2-mediated nascent DNA degradation and replication fork collapse under replication stress. We also identify DDX39A as a RAD51-associated protein that binds to stalled forks and resolves RF-RDs, facilitating proper DNA2-mediated DNA resection and replication fork restart. Excessive dissolution of RF-RDs causes replication fork collapse and genomic instability, while insufficient dissolution of RF-RDs under replication stress increases fork stability, resulting in chemoresistance that can be reversed by eliminating RF-RDs. In summary, we elucidated the prevalence of RF-RDs at replication forks within transcriptionally active regions, revealed their pivotal role in safeguarding replication fork stability, and proposed that targeting RF-RDs holds promise for augmenting chemotherapeutic efficacy.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849562","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

Unlocking transcription-coupled DNA repair with the STK19 key 用 STK19 钥匙打开转录耦合 DNA 修复之门

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-19 DOI: 10.1016/j.molcel.2024.11.027

Jochen Kuper, Caroline Kisker, Bennett Van Houten

引用次数: 0

RNA sensing induced by chromosome missegregation augments anti-tumor immunity

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-19 DOI: 10.1016/j.molcel.2024.11.025

Nobunari Sasaki, Mizuki Homme, Takahiko Murayama, Tatsuya Osaki, Toshiyuki Tenma, Tadaichi An, Yujiro Takegami, Tetsuo Tani, Patrick C. Gedeon, Yoshihisa Kobayashi, Israel Cañadas, David A. Barbie, Ryoji Yao, Shunsuke Kitajima

{"title":"RNA sensing induced by chromosome missegregation augments anti-tumor immunity","authors":"Nobunari Sasaki, Mizuki Homme, Takahiko Murayama, Tatsuya Osaki, Toshiyuki Tenma, Tadaichi An, Yujiro Takegami, Tetsuo Tani, Patrick C. Gedeon, Yoshihisa Kobayashi, Israel Cañadas, David A. Barbie, Ryoji Yao, Shunsuke Kitajima","doi":"10.1016/j.molcel.2024.11.025","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.025","url":null,"abstract":"Viral mimicry driven by endogenous double-stranded RNA (dsRNA) stimulates innate and adaptive immune responses. However, the mechanisms that regulate dsRNA-forming transcripts during cancer therapy remain unclear. Here, we demonstrate that dsRNA is significantly accumulated in cancer cells following pharmacologic induction of micronuclei, stimulating mitochondrial antiviral signaling (MAVS)-mediated dsRNA sensing in conjunction with the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. Activation of cytosolic dsRNA sensing cooperates with double-stranded DNA (dsDNA) sensing to upregulate immune cell migration and antigen-presenting machinery. Tracing of dsRNA-sequences reveals that dsRNA-forming transcripts are predominantly generated from non-exonic regions, particularly in locations proximal to genes exhibiting high chromatin accessibility. Activation of this pathway by pulsed monopolar spindle 1 (MPS1) inhibitor treatment, which potently induces micronuclei formation, upregulates cytoplasmic dsRNA sensing and thus promotes anti-tumor immunity mediated by cytotoxic lymphocyte activation in vivo. Collectively, our findings uncover a mechanism in which dsRNA sensing cooperates with dsDNA sensing to boost immune responses, offering an approach to enhance the efficacy of cancer therapies targeting genomic instability.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849560","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

LncRNAs chaperoning dynamic protein condensates in cancer cells LncRNA 在癌细胞中陪衬动态蛋白质凝聚体

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-19 DOI: 10.1016/j.molcel.2024.11.028

Jiaojiao Hu, Dan Li, Cong Liu

引用次数: 0