Genes & development最新文献_第3页

Cohesin-mediated loop extrusion and enhancer-associated factors additively contribute to Sox2 looping with its distal enhancer. 内聚素介导的环挤压和增强因子相关因素共同促进Sox2与其远端增强因子的环形成。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-14 DOI: 10.1101/gad.353296.125

Moreno Martinovic, Koen D Flach, Marit A C de Kort, Michela Maresca, Hans Teunissen, Ning Qing Liu, Tineke L Lenstra, Elzo de Wit

{"title":"Cohesin-mediated loop extrusion and enhancer-associated factors additively contribute to Sox2 looping with its distal enhancer.","authors":"Moreno Martinovic, Koen D Flach, Marit A C de Kort, Michela Maresca, Hans Teunissen, Ning Qing Liu, Tineke L Lenstra, Elzo de Wit","doi":"10.1101/gad.353296.125","DOIUrl":"https://doi.org/10.1101/gad.353296.125","url":null,"abstract":"Sox2 expression is regulated by a distal enhancer cluster known as the Sox2 control region (SCR). Although Sox2 and the SCR exhibit strong interactions in chromosome conformation capture experiments, acute depletion of cohesin only mildly affects Sox2 transcription. Here we show that continuous restarting of loop extrusion, but not stalling of cohesin at CTCF sites, is involved in the maintenance of the Sox2-SCR loop. While depletion of cohesin or CTCF has only a mild impact on Sox2 gene expression, stabilizing cohesin on the DNA by depleting the cohesin release factor WAPL results in a rapid decrease in expression. Furthermore, using genome editing, we show that a weak enhancer located downstream from the Sox2 gene renders Sox2 expression insensitive to the loss of cohesin stalling at CTCF sites. Finally, through targeted and pleiotropic inhibition of the SCR, we demonstrate that the Sox2-SCR loop is a multicomponent system that depends on cohesin-mediated loop extrusion and enhancer-associated factors. Together, our findings highlight the intricate interplay between enhancer activity and loop extrusion in the establishment and maintenance of chromatin loops in the Sox2 locus.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147689721","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 eukaryotic homology search complex distorts donor DNA structure to probe for homology. 真核生物同源搜索复合物扭曲供体DNA结构以探测同源性。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-06 DOI: 10.1101/gad.353376.125

Mitchell V Woodhouse, Jingyi Hu, Meiling Wu, Jin Qian, James T Inman, Michelle D Wang, J Brooks Crickard

{"title":"The eukaryotic homology search complex distorts donor DNA structure to probe for homology.","authors":"Mitchell V Woodhouse, Jingyi Hu, Meiling Wu, Jin Qian, James T Inman, Michelle D Wang, J Brooks Crickard","doi":"10.1101/gad.353376.125","DOIUrl":"10.1101/gad.353376.125","url":null,"abstract":"Homologous recombination (HR) is a DNA double-strand break repair pathway that facilitates genetic exchange and protects damaged replication forks during DNA synthesis. As a template-based repair process, the successful repair of a double-strand break depends on locating suitable homology from a donor DNA sequence elsewhere in the genome. In eukaryotes, Rad51 catalyzes the homology search in coordination with the ATP-dependent motor protein Rad54. The mechanism by which these two proteins regulate forces on dsDNA substrates during homology search remains unknown. Here, we have utilized single-molecule magnetic tweezers and optical trapping methods to monitor remodeling of the DNA template during the homology search. We found that the activity of Rad51 and Rad54 remodels the donor DNA substrate to control the association and dissociation of Rad51-ssDNA filaments in the absence of DNA homology. The mechanism is through the generation of short, isolated, underwound DNA loops extruded by the homology search complex composed of Rad51 and Rad54. Finally, failure of Rad54 to act processively disrupts target selection in vivo. This study provides a basic understanding of how motorized homology search manipulates the donor DNA during the search for a suitable repair template.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multiomic analysis of clonal development reveals new regulators of leukemic cell growth. 克隆发育的多组学分析揭示白血病细胞生长的新调控因子。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353186.125

Gracia Bonilla, Alexander Morris, Sharmistha Kundu, Anthony DuCasse, Grace Kirkpatrick, Jelena Milosevic, Nathan E Jeffries, Kashish Chetal, Emma E Yvanovich, Ting Zhao, Jun Xia, Rana Barghout, David Scadden, Michael K Mansour, Robert E Kingston, David B Sykes, Francois E Mercier, Ruslan I Sadreyev

{"title":"Multiomic analysis of clonal development reveals new regulators of leukemic cell growth.","authors":"Gracia Bonilla, Alexander Morris, Sharmistha Kundu, Anthony DuCasse, Grace Kirkpatrick, Jelena Milosevic, Nathan E Jeffries, Kashish Chetal, Emma E Yvanovich, Ting Zhao, Jun Xia, Rana Barghout, David Scadden, Michael K Mansour, Robert E Kingston, David B Sykes, Francois E Mercier, Ruslan I Sadreyev","doi":"10.1101/gad.353186.125","DOIUrl":"10.1101/gad.353186.125","url":null,"abstract":"Mechanisms driving the increase in cell growth in developing leukemia are not fully understood. We focused on epigenomic regulation of this process by analyzing the changes of chromatin marks and gene expression in leukemic cell clones as they progressed toward increased proliferation in a mouse model of acute myeloid leukemia (AML). This progression was characterized by gradual modulation of chromatin states and gene expression across the genome, with a surprising preferential trend of reversing the prior changes associated with the origins of leukemia. Our analyses of this modulation in independently developing clones predicted a small set of potential growth regulators whose transcriptomic and epigenomic progression was consistent between clones and maintained both in vivo and ex vivo. We selected three of these genes as candidates (Irx5 and Plag1 as growth suppressors and Smad1 as a driver) and successfully validated their causal growth effects by overexpression in mouse leukemic cells. Overexpression of the IRX5 gene in human MOLM13 leukemic cells suppressed cell growth both in vitro and in mouse xenografts. Public patient data confirmed expression levels of PLAG1 and SMAD1 as markers of AML status and survival, suggesting that multiomic analysis of evolving clones in a mouse model is a valuable predictive approach relevant to human AML.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"563-585"},"PeriodicalIF":7.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13041715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bypass of blocking lesions by RNAPII reveals a novel stress induced by DNA damage. RNAPII旁路阻断病变揭示了由DNA损伤引起的一种新的应激。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353164.125

Carolina P Bañuelos, Lucas D Caeiro, Pradeepkumar R Cingaram, Felipe Beckedorff, Lluis Morey, Daniel Bilbao Cortes, Ramin Shiekhattar, Ramiro E Verdun

{"title":"Bypass of blocking lesions by RNAPII reveals a novel stress induced by DNA damage.","authors":"Carolina P Bañuelos, Lucas D Caeiro, Pradeepkumar R Cingaram, Felipe Beckedorff, Lluis Morey, Daniel Bilbao Cortes, Ramin Shiekhattar, Ramiro E Verdun","doi":"10.1101/gad.353164.125","DOIUrl":"10.1101/gad.353164.125","url":null,"abstract":"Platinum-based compounds and ultraviolet (UV) irradiation produce bulky DNA lesions that stall RNA polymerase II (RNAPII), activating transcription-coupled nucleotide excision repair (TC-NER), RNAPII degradation, and global transcriptional shutdown. However, the consequences of RNAPII bypassing such lesions remain unclear. We identified the acetyltransferase p300 as a key regulator of TC-NER-dependent RNAPII removal from damaged chromatin via a USP7-dependent mechanism. Loss of p300 permits RNAPII to bypass transcription-blocking lesions, sustaining transcription and full-length mRNA production despite DNA damage. This leads to continued translation, endoplasmic reticulum (ER) stress, and activation of the unfolded protein response (UPR), compromising cell viability. Notably, this stress response resensitizes tumors resistant to platinum-based chemotherapy. Our findings reveal a vulnerability in tumor cells that evade transcriptional shutdown and define a synthetic lethal interaction between p300 inhibition and platinum-induced DNA damage, offering a targeted strategy to overcome chemoresistance.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"538-562"},"PeriodicalIF":7.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146124586","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

It takes two to cleave: the logic of cluster assistance. 分裂需要两个因素：集群援助的逻辑。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353586.125

Owen Sanborn, Daniel Cifuentes

引用次数: 0

A brain-specific microRNA, miR-1000, regulates lipid homeostasis via neuropeptide-like precursor 1 in Drosophila melanogaster. 一种脑特异性microRNA miR-1000通过神经肽样前体1调节黑腹果蝇的脂质稳态。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353195.125

Pushpa Verma, Pruthvi Gowda, Nika N Danial, David Van Vactor

引用次数: 0

Exosome-mediated decay of unstable long extended precursors of human telomerase RNA is dependent on 5'-cap trimethylation. 外泌体介导的不稳定的长端粒酶RNA前体的衰变依赖于5'-帽三甲基化。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353100.125

Aniruddha Samajdar, Roberta Amato, Seongmoon Jo, Ethan Cordes, Albert Tai, Grazia Daniela Raffa, Luis F Z Batista

{"title":"Exosome-mediated decay of unstable long extended precursors of human telomerase RNA is dependent on 5'-cap trimethylation.","authors":"Aniruddha Samajdar, Roberta Amato, Seongmoon Jo, Ethan Cordes, Albert Tai, Grazia Daniela Raffa, Luis F Z Batista","doi":"10.1101/gad.353100.125","DOIUrl":"10.1101/gad.353100.125","url":null,"abstract":"Mutations that impact maturation of human telomerase RNA (hTR) are common in telomere biology disorders. Here, we describe sequential posttranscriptional modifications that coordinate hTR biogenesis and decay. Initially, TGS1-mediated 5'-cap trimethylation targets long genomically extended hTR precursors for degradation. Prevention of 5'-cap trimethylation results in accumulation of nucleolar 3'-end extended precursors, evading MTR4 recognition and degradation by the exosome. In a second step, 3'-end oligoadenylation by PAPD5 promotes degradation of mature hTR, a process that remains dependent on 5'-cap modifications, as prevention of trimethylation inhibits decay of heavily 3'-end oligoadenylated molecules. Combined inhibition of 5'-cap trimethylation and 3'-end oligoadenylation synergistically increases hTR in cells harboring pathogenic mutations in telomerase. These data reveal a precise interplay between 5'- and 3'-end posttranscriptional modifications that dictate hTR fate and highlight the potential of RNA therapeutics for treatment of telomere biology disorders.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"498-516"},"PeriodicalIF":7.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13041540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The LINC complex component Kms1 and CENP-B protein Cbp1 cooperate to enforce faithful homology-directed DNA repair at the nuclear periphery in S. pombe. LINC复合物组分Kms1和CENP-B蛋白Cbp1合作，在pombe的核外周进行忠实的同源定向DNA修复。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353167.125

Alyssa Laffitte, Dongxu Lin, Yingzhen Jenny Tian, Na Liu, C Patrick Lusk, Simon G J Mochrie, Megan C King

{"title":"The LINC complex component Kms1 and CENP-B protein Cbp1 cooperate to enforce faithful homology-directed DNA repair at the nuclear periphery in S. pombe.","authors":"Alyssa Laffitte, Dongxu Lin, Yingzhen Jenny Tian, Na Liu, C Patrick Lusk, Simon G J Mochrie, Megan C King","doi":"10.1101/gad.353167.125","DOIUrl":"10.1101/gad.353167.125","url":null,"abstract":"While homologous recombination (HR) is often considered to be an error-free DNA repair mechanism, the fidelity of this pathway depends on the cell's ability to engage the ideal template: the replicated sister chromatid. This is particularly challenging during repair of repetitive genome regions for which nonallelic sequences can errantly be used as templates. We developed a model to study spontaneous DNA damage and repair that occurs at repetitive protein-coding genes of the Schizosaccharomyces pombe flocculin family. We observed that genes encoding most members of this protein family constitutively reside at the nuclear periphery by virtue of their close proximity to binding sites for the CENP-B-like protein, Cbp1. Tethering via Cbp1 to the nuclear periphery enhances the stability of the flocculin genes against intragenic recombination and restrains intergenic recombination between homoeologous repeat-encoding sequences. The LINC complex component Kms1 also antagonizes both intragenic and intergenic recombination at the flocculin genes as well as microhomology-mediated end joining (MMEJ). Our observations suggest that S. pombe leverages nuclear compartmentalization to maintain the stability of repetitive genic regions at the nuclear periphery, while association of DSBs with Kms1-containing LINC complexes enforces stringency to avoid mutagenic end joining and use of the incorrect template during HR.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"456-474"},"PeriodicalIF":7.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13041547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nonhomologous end joining-the importance of end tethering and beyond. 非同源端连接——端系的重要性及以后。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353407.125

Shan Zha, Geunil Yi

{"title":"Nonhomologous end joining-the importance of end tethering and beyond.","authors":"Shan Zha, Geunil Yi","doi":"10.1101/gad.353407.125","DOIUrl":"10.1101/gad.353407.125","url":null,"abstract":"The nonhomologous end joining (NHEJ) pathway is a major mechanism for repairing DNA double-strand breaks (DSBs), essential for lymphocyte development and for maintaining genome stability in postmitotic cells, including neurons. Under pathological conditions, NHEJ is also responsible for most oncogenic translocations and the repair of DSBs induced by chemotherapy/radiation. Advances in structural biology and single-molecule imaging have captured NHEJ at various stages of the reaction, revealing a modular, dynamic organization with built-in redundancy and resilience. Here, we describe NHEJ in five phases (end sensing, end protection, end tethering, end processing, and end ligation), highlighting their molecular features and transitions and how structural insights explain genetic interactions and physiological consequences, including lymphocyte development. Unlike other DSB repair mechanisms, NHEJ operates with minimal or no sequence complementarity, relying instead on protein assemblies to bridge and stabilize the two DNA ends. This review highlights the unique end-tethering phase, supported by at least five known overlapping machineries, all anchored on Ku.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"411-428"},"PeriodicalIF":7.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13041557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

tRNA synthetase activity is required for stress granule and P-body assembly. tRNA合成酶活性是胁迫颗粒和p体组装所必需的。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353535.125

Max Baymiller, Noah S Helton, Benjamin Dodd, Stephanie L Moon

{"title":"tRNA synthetase activity is required for stress granule and P-body assembly.","authors":"Max Baymiller, Noah S Helton, Benjamin Dodd, Stephanie L Moon","doi":"10.1101/gad.353535.125","DOIUrl":"10.1101/gad.353535.125","url":null,"abstract":"Translation elongation defects activate the integrated stress response (ISR), but whether and how ribosome stalls are cleared to enable mRNA release for ribonucleoprotein (RNP) granule assembly remain unclear. We show that blocking tRNA aminoacylation generates persistent uncollided ribosome stalls that inhibit stress granule and P-body assembly despite robust ISR activation. Collided ribosomes are rapidly cleared by ZNF598-dependent ribosome-associated quality control within 4 h, while uncollided stalls resist clearance and persist for >16 h. Puromycin releases persistent stalls and restores RNP granule formation. The block in stress granule assembly is generalizable across tRNA synthetase inhibitors and amino acid deprivation. Therefore, stress granules represent signal integrators reporting translation elongation status when initiation is suppressed. Our findings reveal that translation quality control pathways selectively clear collided ribosomes, establish that translation elongation stress uncouples RNP granule assembly from the ISR, and suggest that tolerating uncollided stalls may be adaptive for cotranslational processes essential for cellular function.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"475-497"},"PeriodicalIF":7.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13041551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0