bioRxiv - Genetics最新文献_第2页

The L1CAM SAX-7 is an antagonistic modulator of Erk signaling L1CAM SAX-7 是 Erk 信号的拮抗调节剂

bioRxiv - Genetics Pub Date : 2024-09-16 DOI: 10.1101/2024.09.14.613091

Melinda Moseley-Alldredge, Caroline Aragon, Marcus Vargus, Divya Alley, Nirali Somia, Lihsia Chen

{"title":"The L1CAM SAX-7 is an antagonistic modulator of Erk signaling","authors":"Melinda Moseley-Alldredge, Caroline Aragon, Marcus Vargus, Divya Alley, Nirali Somia, Lihsia Chen","doi":"10.1101/2024.09.14.613091","DOIUrl":"https://doi.org/10.1101/2024.09.14.613091","url":null,"abstract":"L1CAMs are immunoglobulin superfamily cell adhesion molecules that ensure proper nervous system development and function. In addition to being associated with the autism and schizophrenia spectrum disorders, mutations in the L1CAM family of genes also underlie distinct developmental syndromes with neurological conditions, such as intellectual disability, spastic paraplegia, hypotonia and congenital hydrocephalus. Studies in both vertebrate and invertebrate model organisms have established conserved neurodevelopmental roles for L1CAMs; these include axon guidance, dendrite morphogenesis, synaptogenesis, and maintenance of neural architecture, among others. In Caenorhabditis elegans, L1CAMs, encoded by the sax-7 gene, are required for coordinated locomotion. We previously uncovered a genetic interaction between sax-7 and components of synaptic vesicle cycle, revealing a non-developmental role for sax-7 in regulating synaptic activity. More recently, we determined that sax-7 also genetically interacts with extracellular signal-related kinase (ERK) signaling in controlling coordinated locomotion. C. elegans ERK, encoded by the mpk-1 gene, is a serine/threonine protein kinase belonging to the mitogen-activated protein kinase (MAPK) family that governs multiple aspects of animal development and cellular homeostasis. Here, we show this genetic interaction between sax-7 and mpk-1 occurs not only in cholinergic neurons for coordinated locomotion, but also extends outside the nervous system, revealing novel roles for SAX-7/L1CAM in non-neuronal processes, including vulval development. Our genetic findings in both the nervous system and developing vulva are consistent with SAX-7/L1CAM acting as an antagonistic modulator of ERK signaling.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cross-Tissue Coordination between SLC Nucleoside Transporters Regulates Reproduction in Caenorhabditis elegans SLC 核苷转运体之间的跨组织协调调节秀丽隐杆线虫的繁殖

bioRxiv - Genetics Pub Date : 2024-09-16 DOI: 10.1101/2024.09.12.612591

Youchen Guan, Yong Yu, Shihong Max Gao, Lang Ding, Qian Zhao, Meng Wang

{"title":"Cross-Tissue Coordination between SLC Nucleoside Transporters Regulates Reproduction in Caenorhabditis elegans","authors":"Youchen Guan, Yong Yu, Shihong Max Gao, Lang Ding, Qian Zhao, Meng Wang","doi":"10.1101/2024.09.12.612591","DOIUrl":"https://doi.org/10.1101/2024.09.12.612591","url":null,"abstract":"Metabolism is fundamental to organism physiology and pathology. From the intricate network of metabolic reactions, diverse chemical molecules, collectively termed as metabolites, are produced. In multicellular organisms, metabolite communication between different tissues is vital for maintaining homeostasis and adaptation. However, the molecular mechanisms mediating these metabolite communications remain poorly understood. Here, we focus on nucleosides and nucleotides, essential metabolites involved in multiple cellular processes, and report the pivotal role of the SLC29A family of transporters in mediating nucleoside coordination between the soma and the germline. Through genetic analysis, we discovered that two Caenorhabditis elegans homologs of SLC29A transporters, Equilibrative Nucleoside Transporter ENT-1 and ENT-2, act in the germline and the intestine, respectively, to regulate reproduction. Their knockdown synergistically results in sterility. Further single-cell transcriptomic and targeted metabolomic profiling revealed that the ENT double knockdown specifically affects genes in the purine biosynthesis pathway and reduces the ratio of guanosine to adenosine levels. Importantly, guanosine supplementation into the body cavity/pseudocoelom through microinjection rescued the sterility caused by the ENT double knockdown, whereas adenosine microinjection had no effect. Together, these studies support guanosine as a rate limiting factor in the control of reproduction, uncover the previously unknown nucleoside/nucleotide communication between the soma and the germline essential for reproductive success, and highlight the significance of SLC-mediated cell-nonautonomous metabolite coordination in regulating organism physiology.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"75 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NuRD chromatin remodeling is required to repair exogenous DSBs in the Caenorhabditis elegans germline NuRD染色质重塑是修复秀丽隐杆线虫种系中外源性DSB的必要条件

bioRxiv - Genetics Pub Date : 2024-09-15 DOI: 10.1101/2024.09.14.613027

Deepshikha Ananthaswamy, Kelin Funes, Thiago Borges, Scott P. Roques, Nina Fassnacht, Sereen El Jamal, Paula M. Checchi, Teresa W Lee

{"title":"NuRD chromatin remodeling is required to repair exogenous DSBs in the Caenorhabditis elegans germline","authors":"Deepshikha Ananthaswamy, Kelin Funes, Thiago Borges, Scott P. Roques, Nina Fassnacht, Sereen El Jamal, Paula M. Checchi, Teresa W Lee","doi":"10.1101/2024.09.14.613027","DOIUrl":"https://doi.org/10.1101/2024.09.14.613027","url":null,"abstract":"Organisms rely on coordinated networks of DNA repair pathways to protect genomes against toxic double-strand breaks (DSBs), particularly in germ cells. All repair mechanisms must successfully negotiate the local chromatin environment in order to access DNA. For example, nucleosomes can be repositioned by the highly conserved Nucleosome Remodeling and Deacetylase (NuRD) complex. In Caenorhabditis elegans, NuRD functions in the germline to repair DSBs - the loss of NuRD's ATPase subunit, LET-418/CHD4, prevents DSB resolution and therefore reduces fertility. In this study, we challenge germlines with exogenous DNA damage to better understand NuRD's role in repairing DSBs. We find that let-418 mutants are hypersensitive to cisplatin and hydroxyurea: exposure to either mutagen impedes DSB repair, generates aneuploid oocytes, and severely reduces fertility and embryonic survival. These defects resemble those seen when the Fanconi anemia (FA) DNA repair pathway is compromised, and we find that LET-418's activity is epistatic to that of the FA component FCD-2/FANCD2. We propose a model in which NuRD is recruited to the site of DNA lesions to remodel chromatin and allow access for FA pathway components. Together, these results implicate NuRD in the repair of both endogenous DSBs and exogenous DNA lesions to preserve genome integrity in developing germ cells.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inheritance bias of deletion-harbouring mtDNA in yeast: the role of copy number and intracellular selection 酵母中缺失相邻mtDNA的遗传偏倚：拷贝数和细胞内选择的作用

bioRxiv - Genetics Pub Date : 2024-09-15 DOI: 10.1101/2024.09.11.612442

Nataliia D. Kashko, Iuliia Karavaeva, Elena S. Glagoleva, Maria D. Logacheva, Sofya K. Garushyants, Dmitry A. Knorre

{"title":"Inheritance bias of deletion-harbouring mtDNA in yeast: the role of copy number and intracellular selection","authors":"Nataliia D. Kashko, Iuliia Karavaeva, Elena S. Glagoleva, Maria D. Logacheva, Sofya K. Garushyants, Dmitry A. Knorre","doi":"10.1101/2024.09.11.612442","DOIUrl":"https://doi.org/10.1101/2024.09.11.612442","url":null,"abstract":"Eukaryotic cells contain multiple copies of mitochondrial DNA (mtDNA) molecules that replicate independently. Cell mtDNA content and variability contributes to the overall cell fitness. During sexual reproduction, fungi usually inherit mtDNA from both parents, however, the distribution of the mtDNA in the progeny can be biased toward some mtDNA variants. For example, crossing Saccharomyces cerevisiae strain carrying wild type (rho+) mtDNA with the strain carrying mutant mtDNA variant with large deletion (rho−) can produce up to 99-100% of rho− diploid progeny. Two factors could contribute to this phenomenon. First, rho− cells may accumulate more copies of mtDNA molecules per cell than wild-type cells, making rho− mtDNA a prevalent mtDNA molecule in zygotes. This consequently leads to a high portion of rho− diploid cells in the offspring. Second, rho− mtDNA may have a competitive advantage within heteroplasmic cells, and therefore could displace rho+ mtDNA in a series of generations, regardless of their initial ratio. To assess the contribution of these factors, we investigated the genotypes and phenotypes of twenty two rho− yeast strains. We found that indeed rho− cells have a higher mtDNA copy number per cell than rho+ strains. Using an in silico modelling of mtDNA selection and random drift in heteroplasmic yeast cells, we assessed the intracellular fitness of mutant mtDNA variants. Our model indicates that both higher copy numbers and intracellular fitness advantage of the rho- mtDNA contribute to the biased inheritance of rho− mtDNA.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ripply3 overdosage induces mid-face shortening through Tbx1 downregulation in Down syndrome models. 在唐氏综合征模型中，Ripply3过量会通过Tbx1下调诱导面中部缩短。

bioRxiv - Genetics Pub Date : 2024-09-15 DOI: 10.1101/2024.09.13.612914

Jose Tomas Ahumada Saavedra, Claire Chevalier, Agnes Bloch Zupan, Yann Herault

{"title":"Ripply3 overdosage induces mid-face shortening through Tbx1 downregulation in Down syndrome models.","authors":"Jose Tomas Ahumada Saavedra, Claire Chevalier, Agnes Bloch Zupan, Yann Herault","doi":"10.1101/2024.09.13.612914","DOIUrl":"https://doi.org/10.1101/2024.09.13.612914","url":null,"abstract":"The most frequent and unique features of Down syndrome (DS) are learning disability and craniofacial (CF) dysmorphism. The DS-specific CF features are an overall reduction in head dimensions (microcephaly), relatively wide neurocranium (brachycephaly), reduced mediolaterally orbital region, reduced bizygomatic breadth, small maxilla, small mandible, and increased individual variability. Until now, the cellular and molecular mechanisms underlying the specific craniofacial phenotype have remained poorly understood. Investigating a new panel of DS mouse models with different segmental duplications on mouse chromosome 16 in the region homologous to human chromosome 21, we identified new regions and the role of two candidate gene for DS-specific CF phenotypes. First, we confirmed the role of Dyrk1a in the neurocranium brachycephaly. Then, we identified the role of the transcription factor Ripply3 overdosage in midface shortening through the downregulation of Tbx1, another transcription factor involved in the CF midface phenotype encountered in DiGeorge syndrome. This last effect occurs during branchial arches development through a reduction in cell proliferation. Our findings define a new dosage-sensitive gene responsible for the DS craniofacial features and propose new models for rescuing all aspects of DS CF phenotypes. This data may also provide insights into specific brain and cardiovascular phenotypes observed in DiGeorge and DS models, opening avenues for potential targeted treatment to soften craniofacial dysmorphism in Down syndrome.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery and functional analysis of a novel ALPK1 variant causing ROSAH syndrome 导致 ROSAH 综合征的新型 ALPK1 变异的发现和功能分析

bioRxiv - Genetics Pub Date : 2024-09-15 DOI: 10.1101/2024.09.13.612837

Tom Snelling, Leo Olory-Garnotel, Isabella Jeru, Maud Tusseau, Laurence Cuisset, Antoinette Perlat, Geoffrey Minard, Thibaut Benquey, Yann Maucourant, Nicola T Wood, Philip Cohen, Alban Ziegler

{"title":"Discovery and functional analysis of a novel ALPK1 variant causing ROSAH syndrome","authors":"Tom Snelling, Leo Olory-Garnotel, Isabella Jeru, Maud Tusseau, Laurence Cuisset, Antoinette Perlat, Geoffrey Minard, Thibaut Benquey, Yann Maucourant, Nicola T Wood, Philip Cohen, Alban Ziegler","doi":"10.1101/2024.09.13.612837","DOIUrl":"https://doi.org/10.1101/2024.09.13.612837","url":null,"abstract":"ROSAH syndrome is an autosomal dominant autoinflammatory disorder characterised by visual disturbance caused by pathogenic variation in the protein kinase ALPK1. Only two such variants have been reported to cause ROSAH syndrome to date: 66 out of 67 patients harbour the Thr237Met variant, while a single patient carries a Tyr254Cys variant. Here we identify a family in which ROSAH syndrome is caused by a Ser277Phe variant in ALPK1. The phenotypic variability in this family is high, with four of the seven individuals legally blind. Hypohidrosis, splenomegaly and arthritis were present in several family members. In contrast to wildtype ALPK1, which is activated specifically by the bacterial metabolite ADP-heptose during bacterial infection, ALPK1[Ser277Phe] was also activated by the human metabolites UDP-mannose and ADP-ribose, even more strongly than the ALPK1[Thr237Met] variant. However, unlike ALPK1[Thr237Met], ALPK1[Ser277Phe] could additionally be activated by GDP-mannose. These observations can explain why these ALPK1 variants are active in cells in the absence of ADP-heptose and hence why patients have episodes of autoinflammation. Examination of the three-dimensional structure of ALPK1 revealed that the sidechains of Ser277 and Tyr254 interact but mutational analysis established that this interaction is not critical for the integrity of the ADP-heptose binding site. Instead, it is the replacement of Ser277 by a large hydrophobic phenylalanine residue or the replacement of Tyr254 by a much smaller cysteine residue that is responsible for altering the specificity of the ADP-heptose-binding pocket. The characterisation of ALPK1 variants that cause ROSAH syndrome suggests ways in which drugs that inhibit these disease- causing variants selectively can be developed.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Comprehensive Proteogenomic and Spatial Analysis of Innate and Acquired Resistance of Metastatic Melanoma to Immune Checkpoint Blockade Therapies 转移性黑色素瘤对免疫检查点阻断疗法的先天和后天耐药性的蛋白质组学和空间综合分析

bioRxiv - Genetics Pub Date : 2024-09-15 DOI: 10.1101/2024.09.12.612675

shiyou wei, Kuang Du, Hongbin Lan, Zhenyu Yang, Yulan Deng, Zhi Wei, Dennie T Frederick, Jinho Lee, Marilyne Labrie, Tian Tian, Tabea Moll, Yeqing Chen, Ryan J. Sullivan, Gordon B Mills, Genevieve M Boland, Keith Flaherty, lunxu liu, Meenhard Herlyn, Gao Zhang

{"title":"A Comprehensive Proteogenomic and Spatial Analysis of Innate and Acquired Resistance of Metastatic Melanoma to Immune Checkpoint Blockade Therapies","authors":"shiyou wei, Kuang Du, Hongbin Lan, Zhenyu Yang, Yulan Deng, Zhi Wei, Dennie T Frederick, Jinho Lee, Marilyne Labrie, Tian Tian, Tabea Moll, Yeqing Chen, Ryan J. Sullivan, Gordon B Mills, Genevieve M Boland, Keith Flaherty, lunxu liu, Meenhard Herlyn, Gao Zhang","doi":"10.1101/2024.09.12.612675","DOIUrl":"https://doi.org/10.1101/2024.09.12.612675","url":null,"abstract":"While a subset of patients with metastatic melanoma achieves durable responses to immune checkpoint blockade (ICB) therapies, the majority ultimately exhibit either innate or acquired resistance to these treatments. However, the molecular mechanisms underlying resistance to ICB therapies remain elusive and are warranted to elucidate. Here, we comprehensively investigated the tumor and tumor immune microenvironment (TIME) of paired pre- and post-treatment tumor specimens from metastatic melanoma patients who were primary or secondary resistance to anti-CTLA-4 and/or anti-PD-1/PD-L1 therapies. Differentially expressed gene (DEG) analysis and single-sample gene set enrichment analysis (ssGSEA) with transcriptomic data identified cell cycle and c-MYC signaling as pathway-based resistance signatures. And weighted gene co-expression network analysis (WGCNA) revealed the activation of a cross-resistance meta-program involving key signaling pathways related to tumor progression in ICB resistant melanoma. Moreover, spatially-resolved, image-based immune monitoring analysis by using NanoString digital spatial profiling (DSP) and Cyclic Immunofluorescence (CyCIF) showed infiltration of suppressive immune cells in the tumor microenvironment of melanoma with resistance to ICB therapies. Our study reveals the molecular mechanisms underlying resistance to ICB therapies in patients with metastatic melanoma by conducting such integrated analyses of multi-dimensional data, and provides rationale for salvage therapies that will potentially overcome resistance to ICB therapies.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Homoploid Hybridization Resolves the Origin of Octoploid Strawberries 同源杂交解决了八倍体草莓的起源问题

bioRxiv - Genetics Pub Date : 2024-09-15 DOI: 10.1101/2024.09.12.612680

Zhen Fan, Aaron Liston, Douglas Soltis, Pamela Sue Soltis, Tia-Lynn Ashman, Vance M Whitaker

引用次数: 0

SMARCAD1 Regulates R-Loops at Active Replication Forks Linked to Cancer Mutation Hotspots SMARCAD1 在与癌症突变热点有关的活跃复制叉上调控 R 环

bioRxiv - Genetics Pub Date : 2024-09-15 DOI: 10.1101/2024.09.13.612941

Sidrit Uruci, Nicole M Hoitsma, Maria E. Soler-Oliva, Aleix Bayona-Feliu, Vincent Gaggioli, Maria L. Garcia Rubio, Calvin S.Y. Lo, Collin Bakker, Jessica Marinello, Eleni Maria Manolika, Giovanni Capranico, Martijn S. Luijsterburg, Karolin Luger, Andres Aguilera, Nitika Taneja

{"title":"SMARCAD1 Regulates R-Loops at Active Replication Forks Linked to Cancer Mutation Hotspots","authors":"Sidrit Uruci, Nicole M Hoitsma, Maria E. Soler-Oliva, Aleix Bayona-Feliu, Vincent Gaggioli, Maria L. Garcia Rubio, Calvin S.Y. Lo, Collin Bakker, Jessica Marinello, Eleni Maria Manolika, Giovanni Capranico, Martijn S. Luijsterburg, Karolin Luger, Andres Aguilera, Nitika Taneja","doi":"10.1101/2024.09.13.612941","DOIUrl":"https://doi.org/10.1101/2024.09.13.612941","url":null,"abstract":"DNA replication often encounters obstacles like the stalled transcription machinery and R-loops. While ribonucleases and DNA-RNA helicases can resolve these structures, the role of chromatin remodelers remains understudied. Through a series of in vitro and in vivo experiments, we show that the chromatin remodeler SMARCAD1, which associates with active replication forks, is crucial for resolving nearby R-loops to maintain fork stability. SMARCAD1 directly binds R-loops via its ATPase domain and associates with the replisome through its N-terminus region. Both interactions are critical for resolving R-loops within cells. Genome-wide assays reveal that cells expressing mutant SMARCAD1 accumulate significantly more R-loops than wild-type cells, particularly in regions distinct from known fork blockage-prone sites. These R-loop-enriched regions in SMARCAD1 mutants also exhibit increased mutagenesis in germline tumors, suggesting they are mutation hotspots in cancer. Therefore, SMARCAD1 acts as an R-loop sensor and resolvase at actively progressing forks, maintaining genome stability and preventing tumorigenesis.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multifaceted roles of H2B mono-ubiquitylation in D-loop metabolism during homologous recombination repair 同源重组修复过程中 H2B 单泛素化在 D 环代谢中的多方面作用

bioRxiv - Genetics Pub Date : 2024-09-15 DOI: 10.1101/2024.09.13.612919

Shih-Hsun Hung, Yuan Liang, Wolf Dietrich Heyer

{"title":"Multifaceted roles of H2B mono-ubiquitylation in D-loop metabolism during homologous recombination repair","authors":"Shih-Hsun Hung, Yuan Liang, Wolf Dietrich Heyer","doi":"10.1101/2024.09.13.612919","DOIUrl":"https://doi.org/10.1101/2024.09.13.612919","url":null,"abstract":"Repairing DNA double-strand breaks is crucial for maintaining genome integrity, which occurs primarily through homologous recombination (HR) in S. cerevisiae. Nucleosomes, composed of DNA wrapped around a histone octamer, present a natural barrier to end-resection to initiate HR, but the impact on the downstream HR steps of homology search, DNA strand invasion and repair synthesis remain to be determined. Displacement loops (D-loops) play a pivotal role in HR, yet the influence of chromatin dynamics on D-loop metabolism remains unclear. Using the physical D-loop capture (DLC) and D-loop extension (DLE) assays to track HR intermediates, we employed genetic analysis to reveal that H2B mono-ubiquitylation (H2Bubi) affects multiple steps during HR repair. We infer that H2Bubi modulates chromatin structure, not only promoting histone degradation for nascent D-loop formation but also stabilizing extended D-loops through nucleosome assembly. Furthermore, H2Bubi regulates DNA resection via Rad9 recruitment to suppress a feedback control mechanism that dampens D-loop formation and extension at hyper-resected ends. Through physical and genetic assays to determine repair outcomes, we demonstrate that H2Bubi plays a crucial role in preventing break-induced replication and thus promoting genomic stability.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0