Genes & development最新文献_第2页

MRN–CtIP, EXO1, and DNA2–WRN/BLM act bidirectionally to process DNA gaps in PARPi-treated cells without strand cleavage

IF 10.5 1区生物学

Genes & development Pub Date : 2025-03-24 DOI: 10.1101/gad.352421.124

Isabelle M. Seppa, Ilaria Ceppi, Mithila Tennakoon, Giordano Reginato, Jessica Jackson, Celia D. Rouault, Sumedha Agashe, Vladislav O. Sviderskiy, Mangsi Limbu, Erica Lantelme, Alice Meroni, Stefan Braunshier, Damiano Borrello, Priyanka Verma, Petr Cejka, Alessandro Vindigni

{"title":"MRN–CtIP, EXO1, and DNA2–WRN/BLM act bidirectionally to process DNA gaps in PARPi-treated cells without strand cleavage","authors":"Isabelle M. Seppa, Ilaria Ceppi, Mithila Tennakoon, Giordano Reginato, Jessica Jackson, Celia D. Rouault, Sumedha Agashe, Vladislav O. Sviderskiy, Mangsi Limbu, Erica Lantelme, Alice Meroni, Stefan Braunshier, Damiano Borrello, Priyanka Verma, Petr Cejka, Alessandro Vindigni","doi":"10.1101/gad.352421.124","DOIUrl":"https://doi.org/10.1101/gad.352421.124","url":null,"abstract":"Single-stranded DNA (ssDNA) gaps impact genome stability and PARP inhibitor (PARPi) sensitivity, especially in BRCA1/2-deficient tumors. Using single-molecule DNA fiber analysis, electron microscopy, and biochemical methods, we found that MRN, CtIP, EXO1, and DNA2–WRN/BLM resect ssDNA gaps through a mechanism different from their actions at DNA ends. MRN resects ssDNA gaps in the 3′-to-5′ direction using its pCtIP-stimulated exonuclease activity. Unlike at DNA ends, MRN does not use its endonucleolytic activity to cleave the 5′-terminated strand flanking the gap or the ssDNA. EXO1 and DNA2–WRN/BLM specifically resect the 5′ end of the gap independent of MRN–CtIP. This resection process alters ssDNA gap repair kinetics in BRCA1-proficient and -deficient cells. In BRCA1-deficient cells treated with PARPis, excessive resection results in larger ssDNA gaps, hindering their repair and leading to DNA breaks in subsequent cell cycle stages due to ssDNA gaps colliding with DNA replication forks. These findings broaden our understanding of the role of human nucleases in DNA metabolism and have significant implications for defining the mechanisms driving PARPi sensitivity in BRCA-deficient tumors.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"21 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695668","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

Diverse influences on tau aggregation and implications for disease progression

IF 10.5 1区生物学

Genes & development Pub Date : 2025-03-20 DOI: 10.1101/gad.352551.124

Meaghan Van Alstyne, James Pratt, Roy Parker

引用次数: 0

From fat to fear: how lipid powers cancer spread

IF 10.5 1区生物学

Genes & development Pub Date : 2025-03-14 DOI: 10.1101/gad.352753.125

Lionel Larue

引用次数: 0

MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore

IF 10.5 1区生物学

Genes & development Pub Date : 2025-03-14 DOI: 10.1101/gad.352498.124

Shawn C. Massoni, Nicola J. Evans, Ingo Hantke, Colleen Fenton, James H. Torpey, Katherine M. Collins, Ewelina M. Krysztofinska, Janina H. Muench, Arjun Thapaliya, Santiago Martínez-Lumbreras, Sé Hart Ferrell, Celia Slater, Xinyue Wang, Ruth Fekade, Sandra Obwar, Siyu Yin, Alishba Vazquez, Christopher B. Prior, Kürşad Turgay, Rivka L. Isaacson, Amy H. Camp

{"title":"MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore","authors":"Shawn C. Massoni, Nicola J. Evans, Ingo Hantke, Colleen Fenton, James H. Torpey, Katherine M. Collins, Ewelina M. Krysztofinska, Janina H. Muench, Arjun Thapaliya, Santiago Martínez-Lumbreras, Sé Hart Ferrell, Celia Slater, Xinyue Wang, Ruth Fekade, Sandra Obwar, Siyu Yin, Alishba Vazquez, Christopher B. Prior, Kürşad Turgay, Rivka L. Isaacson, Amy H. Camp","doi":"10.1101/gad.352498.124","DOIUrl":"https://doi.org/10.1101/gad.352498.124","url":null,"abstract":"Bacterial protein degradation machinery consists of chaperone–protease complexes that play vital roles in bacterial growth and development and have sparked interest as novel antimicrobial targets. ClpC–ClpP (ClpCP) is one such chaperone–protease complex, recruited by adaptors to specific functions in the model bacterium Bacillus subtilis and other Gram-positive bacteria, including the pathogens Staphylococcus aureus and Mycobacterium tuberculosis. Here we have identified a new ClpCP adaptor protein, MdfA (metabolic differentiation factor A; formerly YjbA), in a genetic screen for factors that help drive B. subtilis toward metabolic dormancy during spore formation. A knockout of mdfA stimulates gene expression in the developing spore, while aberrant expression of mdfA during vegetative growth is toxic. MdfA binds directly to ClpC to induce its oligomerization and ATPase activity, and this interaction is required for the in vivo effects of mdfA. Finally, a cocrystal structure reveals that MdfA binds to the ClpC N-terminal domain at a location analogous to that on the M. tuberculosis ClpC1 protein where bactericidal cyclic peptides bind. Altogether, our data and that of an accompanying study by Riley and colleagues support a model in which MdfA induces ClpCP-mediated degradation of metabolic enzymes in the developing spore, helping drive it toward metabolic dormancy.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"89 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627430","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

Where and why have so many metabolic enzymes gone from developing spores of Bacillus subtilis?

IF 10.5 1区生物学

Genes & development Pub Date : 2025-03-14 DOI: 10.1101/gad.352755.125

Peter Setlow

引用次数: 0

Developmentally regulated proteolysis by MdfA and ClpCP mediates metabolic differentiation during Bacillus subtilis sporulation

IF 10.5 1区生物学

Genes & development Pub Date : 2025-03-14 DOI: 10.1101/gad.352535.124

Eammon P. Riley, Jelani A. Lyda, Octavio Reyes-Matte, Joseph Sugie, Iqra R. Kasu, Eray Enustun, Emily G. Armbruster, Sumedha Ravishankar, Rivka L. Isaacson, Amy H. Camp, Javier Lopez-Garrido, Kit Pogliano

{"title":"Developmentally regulated proteolysis by MdfA and ClpCP mediates metabolic differentiation during Bacillus subtilis sporulation","authors":"Eammon P. Riley, Jelani A. Lyda, Octavio Reyes-Matte, Joseph Sugie, Iqra R. Kasu, Eray Enustun, Emily G. Armbruster, Sumedha Ravishankar, Rivka L. Isaacson, Amy H. Camp, Javier Lopez-Garrido, Kit Pogliano","doi":"10.1101/gad.352535.124","DOIUrl":"https://doi.org/10.1101/gad.352535.124","url":null,"abstract":"Bacillus subtilis sporulation entails a dramatic transformation of the two cells required to assemble a dormant spore, with the larger mother cell engulfing the smaller forespore to produce the “cell within a cell” structure that is a hallmark of endospore formation. Sporulation also entails metabolic differentiation, whereby key metabolic enzymes are depleted from the forespore but maintained in the mother cell. This reduces the metabolic potential of the forespore, which becomes dependent on mother cell metabolism and the SpoIIQ–SpoIIIA channel to obtain metabolic building blocks necessary for development. We demonstrate that metabolic differentiation depends on the ClpCP protease and a forespore-produced protein encoded by the yjbA gene, which we have renamed MdfA (metabolic differentiation factor A). MdfA is conserved in aerobic endospore formers and required for spore resistance to hypochlorite. Using mass spectrometry and quantitative fluorescence microscopy, we show that MdfA mediates the depletion of dozens of metabolic enzymes and key transcription factors from the forespore. An accompanying study by Massoni and colleagues demonstrates that MdfA is a ClpC adaptor protein that directly interacts with and stimulates ClpCP activity. Together, these results document a developmentally regulated proteolytic pathway that reshapes forespore metabolism, reinforces differentiation, and enhances spore resistance to the oxidant hypochlorite.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"23 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627423","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

Active telomere elongation by a subclass of cancer-associated POT1 mutations

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-27 DOI: 10.1101/gad.352492.124

Annika Martin, Johannes Schabort, Rebecca Bartke-Croughan, Stella Tran, Atul Preetham, Robert Lu, Richard Ho, Jianpu Gao, Shirin Jenkins, John Boyle, George E. Ghanim, Milind Jagota, Yun S. Song, Hanqin Li, Dirk Hockemeyer

{"title":"Active telomere elongation by a subclass of cancer-associated POT1 mutations","authors":"Annika Martin, Johannes Schabort, Rebecca Bartke-Croughan, Stella Tran, Atul Preetham, Robert Lu, Richard Ho, Jianpu Gao, Shirin Jenkins, John Boyle, George E. Ghanim, Milind Jagota, Yun S. Song, Hanqin Li, Dirk Hockemeyer","doi":"10.1101/gad.352492.124","DOIUrl":"https://doi.org/10.1101/gad.352492.124","url":null,"abstract":"Mutations in the shelterin protein POT1 are associated with diverse cancers and thought to drive carcinogenesis by impairing POT1's suppression of aberrant telomere elongation. To classify clinical variants of uncertain significance (VUSs) and identify cancer-driving loss-of-function mutations, we developed a locally haploid human stem cell system to evaluate >1900 POT1 mutations, including >600 VUSs. Unexpectedly, many validated familial cancer-associated POT1 (caPOT1) mutations are haplosufficient for cellular viability, indicating that some pathogenic alleles do not act through a loss-of-function mechanism. Instead, POT1's DNA damage response suppression and telomere length control are genetically separable. ATR inhibition enables isolation of frameshift mutants, demonstrating that the only essential function of POT1 is to repress ATR. Furthermore, comparison of caPOT1 and frameshift alleles reveals a class of caPOT1 mutations that elongate telomeres more rapidly than full loss-of-function alleles. This telomere length-promoting activity is independent from POT1's role in overhang sequestration and fill-in synthesis.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"9 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518779","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

The transcription factor SRF regulates MERVL retrotransposons and gene expression during zygotic genome activation

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-27 DOI: 10.1101/gad.352270.124

Clara Hermant, Carlos Michel Mourra-Díaz, Marlies E. Oomen, Luis Altamirano-Pacheco, Mrinmoy Pal, Tsunetoshi Nakatani, Maria-Elena Torres-Padilla

{"title":"The transcription factor SRF regulates MERVL retrotransposons and gene expression during zygotic genome activation","authors":"Clara Hermant, Carlos Michel Mourra-Díaz, Marlies E. Oomen, Luis Altamirano-Pacheco, Mrinmoy Pal, Tsunetoshi Nakatani, Maria-Elena Torres-Padilla","doi":"10.1101/gad.352270.124","DOIUrl":"https://doi.org/10.1101/gad.352270.124","url":null,"abstract":"The regulatory circuitry of cell-specific transcriptional programs is thought to be influenced by transposable elements (TEs), whereby TEs serve as raw material for the diversification and genome-wide distribution of genetic elements that contain cis-regulatory activity. However, the transcriptional activators of TEs in relevant physiological contexts are largely unknown. Here, we undertook an evolutionary approach to identify regulators of two main families of MERVL, a major regulator of transcription during early mouse development. Using a combination of phyloregulatory, transcriptomic, and loss-of-function approaches, we demonstrate that SRF is a novel regulator of MERVL and embryonic transcription during zygotic genome activation. By resolving the phylogenetic history of two major MERVL families, we delineate the evolutionary acquisition of SRF and DUX binding sites and show that the acquisition of the SRF site precedes that of DUX. SRF contributes to embryonic transcription through the regulation of MERVLs, which in turn serve as promoters for host genes. Our work identifies new transcriptional regulators and TEs that shape the gene expression programs in early embryos and highlights the process of TE domestication via the sequential acquisition of transcription factor binding sites and coevolution with the host.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"52 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518777","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

Fatty acid uptake activates an AXL–CAV1–β-catenin axis to drive melanoma progression

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-27 DOI: 10.1101/gad.351985.124

Ana Chocarro-Calvo, Miguel Jociles-Ortega, José Manuel García-Martinez, Pakavarin Louphrasitthiphol, Sofia Carvalho-Marques, Yurena Vivas-García, Ana Ramírez-Sánchez, Jagat Chauhan, M. Carmen Fiuza, Manuel Druan, Adriana Sánchez-Danés, Colin R. Goding, Custodia García-Jiménez

{"title":"Fatty acid uptake activates an AXL–CAV1–β-catenin axis to drive melanoma progression","authors":"Ana Chocarro-Calvo, Miguel Jociles-Ortega, José Manuel García-Martinez, Pakavarin Louphrasitthiphol, Sofia Carvalho-Marques, Yurena Vivas-García, Ana Ramírez-Sánchez, Jagat Chauhan, M. Carmen Fiuza, Manuel Druan, Adriana Sánchez-Danés, Colin R. Goding, Custodia García-Jiménez","doi":"10.1101/gad.351985.124","DOIUrl":"https://doi.org/10.1101/gad.351985.124","url":null,"abstract":"Interaction between the tumor microenvironment and cancer cell plasticity drives intratumor phenotypic heterogeneity and underpins disease progression and nongenetic therapy resistance. Phenotype-specific expression of the AXL receptor tyrosine kinase is a pivotal player in dormancy, invasion, and resistance to treatment. However, although the AXL ligand GAS6 is present within tumors, how AXL is activated in metastasizing cells remains unclear. Here, using melanoma as a model, we reveal that AXL is activated by exposure to human adipocytes and to oleic acid, a monounsaturated fatty acid abundant in lymph and in adipocytes. AXL activation triggers SRC-dependent formation and nuclear translocation of a β-catenin–CAV1 complex required for melanoma invasiveness. Remarkably, only undifferentiated AXLHigh melanoma cells engage in symbiosis with human adipocytes, in part by triggering WNT5a-mediated lipolysis, leading to AXL-dependent, but FATP-independent, fatty acid uptake and nuclear localization of the β-catenin–CAV1 complex. Significantly, human melanomas in the vicinity of adipocytes exhibit high levels of nuclear CAV1. The results unveil an AXL- and CAV1-dependent mechanism through which a nutritional input drives phenotype-specific activation of a prometastasis program. Given the key role of AXL in a broad range of cancers, the results offer major insights into the mechanisms of cancer cell dormancy and therapy resistance.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"33 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518776","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

RNA-binding proteins: it's better to play in a band

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-12 DOI: 10.1101/gad.352667.125

Joshua Jeong, Klemens J. Hertel, Yongsheng Shi

引用次数: 0