Molecular CellPub Date : 2024-08-14DOI: 10.1016/j.molcel.2024.07.019
{"title":"Molecular impact of mutations in RNA splicing factors in cancer","authors":"","doi":"10.1016/j.molcel.2024.07.019","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.07.019","url":null,"abstract":"<p>Somatic mutations in genes encoding components of the RNA splicing machinery occur frequently in multiple forms of cancer. The most frequently mutated RNA splicing factors in cancer impact intronic branch site and 3′ splice site recognition. These include mutations in the core RNA splicing factor SF3B1 as well as mutations in the U2AF1/2 heterodimeric complex, which recruits the SF3b complex to the 3′ splice site. Additionally, mutations in splicing regulatory proteins SRSF2 and RBM10 are frequent in cancer, and there has been a recent suggestion that variant forms of small nuclear RNAs (snRNAs) may contribute to splicing dysregulation in cancer. Here, we describe molecular mechanisms by which mutations in these factors alter splice site recognition and how studies of this process have yielded new insights into cancer pathogenesis and the molecular regulation of splicing. We also discuss data linking mutant RNA splicing factors to RNA metabolism beyond splicing.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981010","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}
Molecular CellPub Date : 2024-08-13DOI: 10.1016/j.molcel.2024.07.020
{"title":"OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response","authors":"","doi":"10.1016/j.molcel.2024.07.020","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.07.020","url":null,"abstract":"<p>Ferroptosis, an iron-dependent form of nonapoptotic cell death mediated by lipid peroxidation, has been implicated in the pathogenesis of multiple diseases. Subcellular organelles play pivotal roles in the regulation of ferroptosis, but the mechanisms underlying the contributions of the mitochondria remain poorly defined. Optic atrophy 1 (OPA1) is a mitochondrial dynamin-like GTPase that controls mitochondrial morphogenesis, fusion, and energetics. Here, we report that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species (ROS) and suppression of an ATF4-mediated integrated stress response. Together, these results identify an OPA1-controlled mitochondrial axis of ferroptosis regulation and provide mechanistic insights for therapeutically manipulating this form of cell death in diseases.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974187","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}
Molecular CellPub Date : 2024-08-13DOI: 10.1016/j.molcel.2024.07.018
{"title":"HLTF resolves G4s and promotes G4-induced replication fork slowing to maintain genome stability","authors":"","doi":"10.1016/j.molcel.2024.07.018","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.07.018","url":null,"abstract":"<p>G-quadruplexes (G4s) form throughout the genome and influence important cellular processes. Their deregulation can challenge DNA replication fork progression and threaten genome stability. Here, we demonstrate an unexpected role for the double-stranded DNA (dsDNA) translocase helicase-like transcription factor (HLTF) in responding to G4s. We show that HLTF, which is enriched at G4s in the human genome, can directly unfold G4s <em>in vitro</em> and uses this ATP-dependent translocase function to suppress G4 accumulation throughout the cell cycle. Additionally, MSH2 (a component of MutS heterodimers that bind G4s) and HLTF act synergistically to suppress G4 accumulation, restrict alternative lengthening of telomeres, and promote resistance to G4-stabilizing drugs. In a discrete but complementary role, HLTF restrains DNA synthesis when G4s are stabilized by suppressing primase-polymerase (PrimPol)-dependent repriming. Together, the distinct roles of HLTF in the G4 response prevent DNA damage and potentially mutagenic replication to safeguard genome stability.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974202","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}
Molecular CellPub Date : 2024-08-09DOI: 10.1016/j.molcel.2024.07.017
{"title":"Nuclear retention coupled with sequential polyadenylation dictates post-transcriptional m6A modification in the nucleus","authors":"","doi":"10.1016/j.molcel.2024.07.017","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.07.017","url":null,"abstract":"<p>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification is deemed to be co-transcriptionally installed on pre-mRNAs, thereby influencing various downstream RNA metabolism events. However, the causal relationship between m<sup>6</sup>A modification and RNA processing is often unclear, resulting in premature or even misleading generalizations on the function of m<sup>6</sup>A modification. Here, we develop 4sU-coupled m<sup>6</sup>A-level and isoform-characterization sequencing (4sU-m<sup>6</sup>A-LAIC-seq) and 4sU-GLORI to quantify the m<sup>6</sup>A levels for both newly synthesized and steady-state RNAs at transcript and single-base-resolution levels, respectively, which enable dissecting the relationship between m<sup>6</sup>A modification and alternative RNA polyadenylation. Unexpectedly, our results show that many m<sup>6</sup>A addition events occur post-transcriptionally, especially on transcripts with high m<sup>6</sup>A levels. Importantly, we find higher m<sup>6</sup>A levels on shorter 3′ UTR isoforms, which likely result from sequential polyadenylation of longer 3′ UTR isoforms with prolonged nuclear dwelling time. Therefore, m<sup>6</sup>A modification can also take place post-transcriptionally to intimately couple with other key RNA metabolism processes to establish and dynamically regulate epi-transcriptomics in mammalian cells.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141909321","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}
Molecular CellPub Date : 2024-08-08DOI: 10.1016/j.molcel.2024.07.014
{"title":"Puff, the polytene chromosome: Visualizing transcription elongation control","authors":"","doi":"10.1016/j.molcel.2024.07.014","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.07.014","url":null,"abstract":"<p>In this issue, Versluis et al.<span><span><sup>1</sup></span></span> use a highly sensitive live-cell imaging system to examine transcription dynamics and functions of various key transcription elongation regulators at the <em>Hsp70</em> loci.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904167","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}
Molecular CellPub Date : 2024-08-08DOI: 10.1016/j.molcel.2024.07.015
{"title":"Decoding the end of message: PASTA provides food for thought on mechanisms of alternative polyadenylation","authors":"","doi":"10.1016/j.molcel.2024.07.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.07.015","url":null,"abstract":"<p>In a recent publication in <em>Cell</em>, Kowalski et al.<span><span><sup>1</sup></span></span> developed an interdisciplinary and multiplexed approach to uncover regulatory modules of alternative polyadenylation, involving single-cell-based gene perturbation, isoform abundance analysis, machine learning of RNA motifs, and massively parallel reporter assays.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904169","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}
Molecular CellPub Date : 2024-08-08DOI: 10.1016/j.molcel.2024.07.010
{"title":"Two HUSH complexes connect a direct LINE to innate immunity","authors":"","doi":"10.1016/j.molcel.2024.07.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.07.010","url":null,"abstract":"<p>In this issue of <em>Molecular Cell</em>, Danac et al.<span><span><sup>1</sup></span></span> identify a second HUSH complex, HUSH2, that represses interferon-stimulated genes and, by competing for subunits with the canonical HUSH complex, couples LINE-1 (L1) retrotransposon transcription with immune activation.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904168","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}
Molecular CellPub Date : 2024-08-08DOI: 10.1016/j.molcel.2024.07.016
{"title":"Structural insights into the cooperative nucleosome recognition and chromatin opening by FOXA1 and GATA4","authors":"","doi":"10.1016/j.molcel.2024.07.016","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.07.016","url":null,"abstract":"<p>Mouse FOXA1 and GATA4 are prototypes of pioneer factors, initiating liver cell development by binding to the N1 nucleosome in the enhancer of the <em>ALB1</em> gene. Using cryoelectron microscopy (cryo-EM), we determined the structures of the free N1 nucleosome and its complexes with FOXA1 and GATA4, both individually and in combination. We found that the DNA-binding domains of FOXA1 and GATA4 mainly recognize the linker DNA and an internal site in the nucleosome, respectively, whereas their intrinsically disordered regions interact with the acidic patch on histone H2A-H2B. FOXA1 efficiently enhances GATA4 binding by repositioning the N1 nucleosome. <em>In vivo</em> DNA editing and bioinformatics analyses suggest that the co-binding mode of FOXA1 and GATA4 plays important roles in regulating genes involved in liver cell functions. Our results reveal the mechanism whereby FOXA1 and GATA4 cooperatively bind to the nucleosome through nucleosome repositioning, opening chromatin by bending linker DNA and obstructing nucleosome packing.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904164","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}
Molecular CellPub Date : 2024-08-08DOI: 10.1016/j.molcel.2024.07.012
{"title":"Meet the authors: Emily R. Feierman and Erica Korb","authors":"","doi":"10.1016/j.molcel.2024.07.012","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.07.012","url":null,"abstract":"<p>We talk to first author Emily R. Feierman and corresponding author Erica Korb about the journey toward their paper “Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory” (this issue of <em>Molecular Cell</em>) and changes smoothing the road for women in science.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904165","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}