Genes & development最新文献_第8页

The ribosome-associated quality control factor TCF25 imposes K48 specificity on Listerin-mediated ubiquitination of nascent chains by binding and specifically orienting the acceptor ubiquitin 核糖体相关质量控制因子TCF25通过结合和特异性定向受体泛素，对新生链的listerin介导的泛素化施加K48特异性

IF 10.5 1区生物学

Genes & development Pub Date : 2025-04-01 DOI: 10.1101/gad.352389.124

Irina S. Abaeva, Alexander G. Bulakhov, Christopher U.T. Hellen, Tatyana V. Pestova

{"title":"The ribosome-associated quality control factor TCF25 imposes K48 specificity on Listerin-mediated ubiquitination of nascent chains by binding and specifically orienting the acceptor ubiquitin","authors":"Irina S. Abaeva, Alexander G. Bulakhov, Christopher U.T. Hellen, Tatyana V. Pestova","doi":"10.1101/gad.352389.124","DOIUrl":"https://doi.org/10.1101/gad.352389.124","url":null,"abstract":"Polypeptides arising from interrupted translation undergo proteasomal degradation by the ribosome-associated quality control (RQC) pathway. The ASC-1 complex splits stalled ribosomes into 40S subunits and nascent chain–tRNA-associated 60S subunits (60S RNCs). 60S RNCs associate with NEMF that promotes recruitment of the RING-type E3 ubiquitin (Ub) ligase Listerin (Ltn1 in yeast), which ubiquitinates nascent chains. RING-type E3s mediate the transfer of Ub directly from the E2∼Ub conjugate, implying that the specificity of Ub linkage is determined by the given E2. Listerin is most efficient when it is paired with promiscuous Ube2D E2s. We previously found that TCF25 (Rqc1 in yeast) can impose K48 specificity on Listerin paired with Ube2D E2s. To determine the mechanism of TCF25's action, we combined functional biochemical studies and AlphaFold3 modeling and now report that TCF25 specifically interacts with the RING domain of Listerin and the acceptor ubiquitin (UbA) and imposes K48 specificity by orienting UbA such that its K48 is directly positioned to attack the thioester bond of the Ube2D1∼Ub conjugate. We also found that TCF25 itself undergoes K48-specific ubiquitination by Listerin, suggesting a mechanism for the reported upregulation of Rqc1 in the absence of Ltn1 and the observed degradation of TCF25 by the proteasome in vivo.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"32 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757781","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

In vivo CRISPR screening reveals epigenetic regulators of hepatobiliary plasticity 体内CRISPR筛选揭示了肝胆可塑性的表观遗传调控因子

IF 10.5 1区生物学

Genes & development Pub Date : 2025-04-01 DOI: 10.1101/gad.352420.124

Jonathan H. Sussman, Hector W. Cure, Salina Yuan, Kenji Ito, Irfan A. Asangani, Benjamin A. Garcia, Ben Z. Stanger, Takeshi Katsuda

{"title":"In vivo CRISPR screening reveals epigenetic regulators of hepatobiliary plasticity","authors":"Jonathan H. Sussman, Hector W. Cure, Salina Yuan, Kenji Ito, Irfan A. Asangani, Benjamin A. Garcia, Ben Z. Stanger, Takeshi Katsuda","doi":"10.1101/gad.352420.124","DOIUrl":"https://doi.org/10.1101/gad.352420.124","url":null,"abstract":"Following prolonged liver injury, a small fraction of hepatocytes undergoes reprogramming to become cholangiocytes or biliary epithelial cells (BECs). This physiological process involves chromatin and transcriptional remodeling, but the epigenetic mediators are largely unknown. Here, we exploited a lineage-traced model of liver injury to investigate the role of histone post-translational modification in biliary reprogramming. Using mass spectrometry, we defined the repertoire of histone marks that are globally altered in quantity during reprogramming. Next, applying an in vivo CRISPR screening approach, we identified seven histone-modifying enzymes that alter the efficiency of hepatobiliary reprogramming. Among these, the histone methyltransferase and demethylase Nsd1 and Kdm2a were found to have reciprocal effects on H3K36 methylation that regulated the early and late stages of reprogramming, respectively. Although loss of Nsd1 and Kdm2a affected reprogramming efficiency, cells ultimately acquired the same transcriptomic states. These findings reveal that multiple chromatin regulators exert dynamic and complementary activities to achieve robust cell fate switching, serving as a model for the cell identity changes that occur in various forms of physiological metaplasia or reprogramming.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"16 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757783","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

Cognition and behavior in neurofibromatosis type 1: report and perspective from the Cognition and Behavior in NF1 (CABIN) Task Force 1型神经纤维瘤病的认知与行为：来自NF1 （CABIN）工作组的认知与行为报告与视角

IF 10.5 1区生物学

Genes & development Pub Date : 2025-03-24 DOI: 10.1101/gad.352629.125

David H. Gutmann, Corina Anastasaki, Aditi Gupta, Yang Hou, Stephanie M. Morris, Jonathan M. Payne, Jacob Raber, Seth M. Tomchik, Linda Van Aelst, James A. Walker, Kaleb H. Yohay, on behalf of the CABIN Task Force

{"title":"Cognition and behavior in neurofibromatosis type 1: report and perspective from the Cognition and Behavior in NF1 (CABIN) Task Force","authors":"David H. Gutmann, Corina Anastasaki, Aditi Gupta, Yang Hou, Stephanie M. Morris, Jonathan M. Payne, Jacob Raber, Seth M. Tomchik, Linda Van Aelst, James A. Walker, Kaleb H. Yohay, on behalf of the CABIN Task Force","doi":"10.1101/gad.352629.125","DOIUrl":"https://doi.org/10.1101/gad.352629.125","url":null,"abstract":"Individuals with neurofibromatosis type 1 (NF1) are prone to the evolution of neurodevelopmental symptomatology including motor delays, learning disabilities, autism, and attention deficits. Caused by heterozygous germline mutations in the NF1 gene, this monogenic condition offers unique opportunities to study the genetic etiologies for neurodevelopmental disorders and the mechanisms that underlie their formation. Although numerous small animal models have been generated to elucidate the causes of these alterations, there is little consensus on how to align preclinical observations with clinical outcomes, harmonize findings across species, and consolidate these insights to chart a cohesive path forward. Capitalizing on expertise from clinicians; human, animal, and cellular model research scientists; and bioinformatics researchers, the first Cognition and Behavior in NF1 (CABIN) meeting was convened at the Banbury Center of Cold Spring Harbor Laboratory in October 2024. This Perspective summarizes the state of our understanding and a proposed plan for future investigation and exploration to improve the quality of life of those with NF1.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"61 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695665","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

MRN–CtIP, EXO1, and DNA2–WRN/BLM act bidirectionally to process DNA gaps in PARPi-treated cells without strand cleavage MRN-CtIP， EXO1和DNA2-WRN /BLM在parpi处理的细胞中双向作用，在没有链切割的情况下加工DNA间隙

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 对tau聚集的不同影响及其对疾病进展的影响

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 从脂肪到恐惧：脂肪如何推动癌症扩散

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 MdfA是一种新型的ClpC接头蛋白，在发育中的枯草芽孢杆菌孢子中起作用

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? 枯草芽孢杆菌孢子发育过程中这么多代谢酶从哪里消失了，为什么消失了？

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 MdfA和ClpCP的发育调节蛋白水解介导枯草芽孢杆菌孢子形成过程中的代谢分化

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 活性端粒延长与癌症相关的POT1突变亚类

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