An integrated genome-wide resource reveals distinct replication environments of DNA breakage in human cancer cell lines
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Le résumé fourni par la source
Abstract Replication stress is a major source of genome instability in cancer, yet the genomic features that determine where DNA double-strand breaks (DSBs) arise remain incompletely defined. Here, we establish an integrated genome-wide resource of DSBs, DNA replication, replication timing, transcription, and R-loops in two widely used cancer cell lines, U2-OS and HeLa, under steady-state conditions and following prolonged low-dose DNA polymerase inhibition. We combine these datasets with systematic statistical testing and comparative analytical approaches to define the replication environments associated with genome fragility. Endogenous DSBs preferentially accumulated at origin-rich initiation zones, where R-loops were enriched, whereas prolonged DNA polymerase inhibition redirected DSB formation toward origin-poor, late-replicating regions. Among the replication features examined, replication initiation zones and late-replicating areas were most sensitive to prolonged replication stress. R-loops were specifically enriched at initiation zones but depleted from late-replicating regions and recurrent DNA break clusters (RDCs), demonstrating that their association with genome fragility is context dependent. Replication stress further induced RDCs within long, actively transcribed genes, while their locations only partially overlapped with common fragile sites. Functional analyses identified MUS81 as a major regulator of RDC formation. MUS81 loss increased RDCs, whereas restoration of its catalytic activity suppressed them, indicating that MUS81 resolves replication intermediates before they persist into late-replicating fragile regions. Together, this resource and analytical framework provide a systematic basis for dissecting how replication architecture, transcription, and DNA processing shape genome fragility in cancer cells.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- An integrated genome-wide resource reveals distinct replication environments of DNA breakage in human cancer cell lines
- Date Crossref
- 15/09/2026
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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German Cancer Research Center pays non établi dans la noticeStructure de recherche
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Heidelberg University pays non établi dans la noticeUniversité ou école supérieure
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Masaryk University pays non établi dans la noticeUniversité ou école supérieure
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Hebrew University of Jerusalem pays non établi dans la noticeUniversité ou école supérieure
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Jerusalem Institute for Israel Studies pays non établi dans la noticeOrganisation à but non lucratif
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Ruprecht Karl University of Heidelberg pays non établi dans la noticeUniversité ou école supérieure
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Faculty of Medicine Department of Biology pays non établi dans la noticeUniversité ou école supérieure
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Faculty of Science NCBR pays non établi dans la noticeUniversité ou école supérieure
German Cancer Research Center, Heidelberg University et Masaryk University, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.