[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-331687-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-331687-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","dna-replication-initiation-drives-focal-mutagenesis-and-rearrangements-in-human-cancers","DNA replication initiation drives focal mutagenesis and rearrangements in human cancers","","Cancer genomes accumulate mutations in patterns shaped by DNA accessibility and ongoing cellular processes. This study shows that efficient DNA replication initiation sites actively regulate specific mutational mechanisms in tumors. Replication initiation impedes nucleotide excision repair in melanoma and acts as off-targets for AICDA activity in lymphomas. In pancreatic adenocarcinoma models, error-prone initiation at G-quadruplex-forming sequences in replication-stress-positive tumors generates a defined mutational signature. Replication origins also function as hotspots for structural and copy number rearrangements, linking initiation to focal mutagenesis and genome instability.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/dna-replication-initiation-drives-focal-mutagenesis-and-rearrangements-in-human-cancers/331687/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/dna-replication-initiation-drives-focal-mutagenesis-and-rearrangements-in-human-cancers/331687.png","ImageObject",300,407,{"name":42,"@type":43},"Aurelia","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-03","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",10,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"How do replication initiation sites affect mutagenesis in cancer genomes?","Question",{"text":63,"@type":64},"Efficient replication initiation sites drive and modulate multiple mutational processes, creating focal mutagenesis patterns. The study links initiation efficiency to specific DNA repair and deamination outcomes across cancer types.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What roles do replication initiation sites play in melanoma and lymphomas?",{"text":68,"@type":64},"In melanoma, initiation sites impede nucleotide excision repair. In lymphomas, these sites act as off-targets for AICDA activity, influencing mutational processes.",{"name":70,"@type":61,"acceptedAnswer":71},"What connection does the study find between replication origins and genomic rearrangements?",{"text":72,"@type":64},"Replication origins serve as hotspots for genomic rearrangements, including structural variations and copy number variations. This supports replication initiation as a functional determinant of tumor genome instability.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},331687,1790180182,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,111,115,120,123,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":108,"show_sort_weight":109,"slug":110},7,"Healthcare",40,"healthcare",{"id":112,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":113,"slug":114},8,30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":55,"slug":125},"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":112,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145,"preview_page_count":4},1099514068365,"https://ap-avatar.wpscdn.com/avatar/10000253d8d9f28188e?x-image-process=image/resize,m_fixed,w_180,h_180&k=1794309523707217728","Article [https://doi.org/10.1038/s41467-024-55148-3](https://doi.org/10.1038/s41467-024-55148-3)  \nDNA replication initiation drives focal mutagenesis and rearrangements in human cancers  \nReceived: 10 April 2024  \n\n| Accepted: 3 December 2024 |\n| --- |\n| |\n| Check for updates |\n\nPierre Murat 1,2 , Guillaume Guilbaud 1 & Julian E. Sale 1   \nThe rate and pattern of mutagenesis in cancer genomes is significantly influenced by DNA accessibility and active biological processes. Here we show that efficient sites of replication initiation drive and modulate specific mutational processes in cancer. Sites of replication initiation impede nucleotide excision repair in melanoma and are off-targets for activation-induced deaminase (AICDA) activity in lymphomas. Using ductal pancreatic adenocarcinoma as a cancer model, we demonstrate that the initiation of DNA synthesis is errorprone at G-quadruplex-forming sequences in tumours displaying markers of replication stress, resulting in a previously recognised but uncharacterised mutational signature. Finally, we demonstrate that replication origins serve as hotspots for genomic rearrangements, including structural and copy number variations. These findings reveal replication origins as functional determinants of tumour biology and demonstrate that replication initiation both passively and actively drives focal mutagenesis in cancer genomes.  \nCancer cells are characterised by their ability to sustain cell growth and proliferation by evading suppressor signals and activating oncogene expression1. The overexpression of oncogenes such as c-Myc, h-RAS, or Cyclin E shortens the G1 phase of the cell cycle, expedites S phase entry, and increases levels of replication initiation2–4. This accelerated S-phase entry is linked to replication stress and genome instability, in part due to origin over-usage and activation of dormant replication origins5. However, the impact of replication initiation on mutagenesisin human cancers has not been examined.  \nWe recently reported that a subset of highly efficient replication origins, conserved across a range of untransformed, immortalised and transformed human cell lines6, act as hotspots for mutagenesis in the germline7. These ‘constitutive’ replication origins are notably enriched within the active and early replicated regions of the human genome, particularly within gene bodies. The mutational processes operating at these sites thus contribute to elevated mutational burdens at gene promoters and splice junctions, impacting phenotypic diversity across human populations. Genomic regions in which replication initiates constitute fragile sites associated with DNA breaks and translocationsin cancer4,8, and origin activity has also been shown to drive  \ntranslocations at the MYC locus in murine B cells, suggesting a potential link between replication origins and the development of lymphomasand other cancers9. Further, increased origin firing contributes to replication stress driven by oncogene activation and is linked to DNA breaks and rearrangements4 while overexpression of origin firing factors such as GINS1 and CDC45 in human colorectal cancer cells leads toaneuploidy10. Collectively, these studies highlight replication origin firing as a cancer-relevant trigger for genome instability.  \nIn this study, we report the identification and characterisation of mutational processes occurring at constitutive origins in cancer. Our results emphasise the major impact of replication initiation in shaping the mutational landscape of the human genome, adding replication origins to the expanding repertoire of genomic features influencing local mutation rates in cancer (reviewed in ref. 11).  \nResults  \nPan-cancer analysis of mutation distribution reveals enrichment at replication origins  \nTo systematically examine the frequency of somatic point mutations at constitutive origins, we considered mutation calls from the  \n1Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Mol","cbCaib6YFETQXnii","https://ap.wps.com/l/cbCaib6YFETQXnii","pdf",3521453,14,"English","# Results\n## Pan-cancer analysis of mutation distribution reveals enrichment at replication origins\n## Identification and characterisation of mutational processes at constitutive origins in cancer","[{\"question\":\"How do replication initiation sites affect mutagenesis in cancer genomes?\",\"answer\":\"Efficient replication initiation sites drive and modulate multiple mutational processes, creating focal mutagenesis patterns. The study links initiation efficiency to specific DNA repair and deamination outcomes across cancer types.\"},{\"question\":\"What roles do replication initiation sites play in melanoma and lymphomas?\",\"answer\":\"In melanoma, initiation sites impede nucleotide excision repair. In lymphomas, these sites act as off-targets for AICDA activity, influencing mutational processes.\"},{\"question\":\"What connection does the study find between replication origins and genomic rearrangements?\",\"answer\":\"Replication origins serve as hotspots for genomic rearrangements, including structural variations and copy number variations. This supports replication initiation as a functional determinant of tumor genome instability.\"}]","DNA replication initiation drives focal mutagenesis and rearrangements in human cancers | PDF",1789994651,35]