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When replication is perturbed, flexibility becomes essential to duplicate the whole genome despite damaged or challenged DNA. This review explains how error-prone polymerases enable continued replication by tolerating replication stress while promoting mutagenesis, a cancer-relevant feature. It further analyzes polymerase usage regulation (e.g., Rad18-mediated PCNA ubiquitylation), linking oncogene-driven stress responses to survival, tumor progression, and exploitable therapeutic dependencies.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/adaptive-use-of-error-prone-dna-polymerases-provides-flexibility-in-genome-replication-during-tumorigenesis/330953/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/adaptive-use-of-error-prone-dna-polymerases-provides-flexibility-in-genome-replication-during-tumorigenesis/330953.png","ImageObject",300,407,{"name":92,"@type":93},"Aria","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why do cells need flexibility during genome replication in tumorigenesis?","Question",{"text":112,"@type":113},"Perturbed replication raises the requirement for flexibility to ensure faithful duplication of the entire genome under challenge. Error-prone polymerases provide this flexibility while enabling replication progression.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do error-prone polymerases contribute to cancer progression?",{"text":117,"@type":113},"They sustain ongoing replication in response to oncogenic mutations that disable key DNA replication and repair pathways, which accelerates mutagenesis and can confer chemoresistance. This also creates a dependency that may be targeted by therapeutics.",{"name":119,"@type":110,"acceptedAnswer":120},"Does misregulated polymerase expression always change polymerase usage in cancers?",{"text":121,"@type":113},"Not necessarily. The review notes that an additional regulatory step may govern polymerase usage even when expression levels are misregulated in cancers.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},330953,1790662771,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":29,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},2336464648322,"https://ap-avatar.wpscdn.com/avatar/2200025388227c56fec?_k=1778556882303663488","DOI: 10. 1111/cas.16188  \nR E V I E W A RT I C L E  \nAdaptive use of error-prone DNA polymerases provides flexibility in genome replication during tumorigenesis  \nLewis J. Bainbridge  | Yasukazu Daigaku   \nCancer Genome Dynamics Project, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan  \nCorrespondence  \nLewis J. Bainbridge and Yasukazu Daigaku, Cancer Genome Dynamics Project, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.  \nEmail: [lewis.bainbridge@jfcr.or.jp](lewis.bainbridge@jfcr.or.jp) and[yasukazu.daigaku@jfcr.or.jp](yasukazu.daigaku@jfcr.or.jp)  \nFunding information  \nYamada Science Foundation; Japan Society for the Promotion of Science, Grant/Award Number: JP23H02463; Takeda Science Foundation; Fusion Oriented REsearch for disruptive Science and Technology, Grant/Award Number: JPMJFR204X; Naito Foundation  \nAbstract  \nHuman cells possess many different polymerase enzymes, which collaborate in conducting DNA replication and genome maintenance to ensure faithful duplication of genetic material. Each polymerase performs a specialized role, together providing a balance of accuracy and flexibility to the replication process. Perturbed replication increases the requirement for flexibility to ensure duplication of the entire genome. Flexibility is provided via the use of error-prone polymerases, which maintain the progression of challenged DNA replication at the expense of mutagenesis, an enabling characteristic of cancer. This review describes our recent understanding of mechanisms that alter the usage of polymerases during tumorigenesis and examines the implications of this for cell survival and tumor progression. Although expression levels of polymerases are often misregulated in cancers, this does not necessarily alter polymerase usage since an additional regulatory step may govern the use of these enzymes. We therefore also examine how the regulatory mechanisms of DNA polymerases, such as Rad18-mediated PCNA ubiquitylation, may impact the functionalization of error-prone polymerases to tolerate oncogene-induced replication stress. Crucially, it is becoming increasingly evident that cancer cells utilize error-prone polymerases to sustain ongoing replication in response to oncogenic mutations which inactivate key DNA replication and repair pathways, such as BRCA deficiency. This accelerates mutagenesis and confers chemoresistance, but also presents a dependency that can potentially be exploited by therapeutics.  \nK E Y WO R D S  \nDNA polymerase, DNA replication, mutagenesis, PCNA ubiquitylation, replication stress  \n1 | INTRODUCTION  \nDNA replication is the essential process for passing genetic information to the next generation and its accuracy and efficiency are  \ncritical factors in maintaining the integrity of the DNA sequence. Inhuman bodies, the loss of replication fidelity leads to somatic mutations and, although most of them are harmless, their steady accumulation can eventually result in phenotypic consequences. Acquired  \nAbbreviations: BRCA, breast cancer gene; CFS, common fragile site; DDT, DNA damage tolerance; DSB, double-strand break; EGFR, epidermal growth factor receptor; HR, homologous recombination; ICL, interstrand crosslink; NHEJ, non-homologous end joining; PCNA, proliferating cell nuclear antigen; Pol, polymerase; SNV, single nucleotide variant; TCGA, The Cancer Genome Atlas; TLS, translesion synthesis; TMEJ, theta-mediated end joining.  \nThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.  \n© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.  \n2126  \nBAINBRIDGE and DAIGAKU  \nmutations in a particular subset of genes represent driver mutations, which confer a selective growth advanta","cbCaibL4PFWnm5Le","https://ap.wps.com/l/cbCaibL4PFWnm5Le","pdf",1244061,13,"English","# Introduction\n## Error-prone polymerases and replication flexibility\n## Polymerase regulation during tumorigenesis","[{\"question\":\"Why do cells need flexibility during genome replication in tumorigenesis?\",\"answer\":\"Perturbed replication raises the requirement for flexibility to ensure faithful duplication of the entire genome under challenge. Error-prone polymerases provide this flexibility while enabling replication progression.\"},{\"question\":\"How do error-prone polymerases contribute to cancer progression?\",\"answer\":\"They sustain ongoing replication in response to oncogenic mutations that disable key DNA replication and repair pathways, which accelerates mutagenesis and can confer chemoresistance. This also creates a dependency that may be targeted by therapeutics.\"},{\"question\":\"Does misregulated polymerase expression always change polymerase usage in cancers?\",\"answer\":\"Not necessarily. The review notes that an additional regulatory step may govern polymerase usage even when expression levels are misregulated in cancers.\"}]","Adaptive use of error-prone DNA polymerases provides flexibility in genome replication during tumorigenesis | PDF",1789990860,33]