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dc.contributor.authorCantor, Sharon B
dc.date.accessioned2023-03-14T16:47:53Z
dc.date.available2023-03-14T16:47:53Z
dc.date.issued2021-08-13
dc.identifier.citationCantor SB. Revisiting the BRCA-pathway through the lens of replication gap suppression: "Gaps determine therapy response in BRCA mutant cancer". DNA Repair (Amst). 2021 Nov;107:103209. doi: 10.1016/j.dnarep.2021.103209. Epub 2021 Aug 13. PMID: 34419699; PMCID: PMC9049047.en_US
dc.identifier.eissn1568-7856
dc.identifier.doi10.1016/j.dnarep.2021.103209en_US
dc.identifier.pmid34419699
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51810
dc.description.abstractThe toxic lesion emanating from chemotherapy that targets the DNA was initially debated, but eventually the DNA double strand break (DSB) ultimately prevailed. The reasoning was in part based on the perception that repairing a fractured chromosome necessitated intricate processing or condemned the cell to death. Genetic evidence for the DSB model was also provided by the extreme sensitivity of cells that were deficient in DSB repair. In particular, sensitivity characterized cells harboring mutations in the hereditary breast/ovarian cancer genes, BRCA1 or BRCA2, that function in the repair of DSBs by homologous recombination (HR). Along with functions in HR, BRCA proteins were found to prevent DSBs by protecting stalled replication forks from nuclease degradation. Coming full-circle, BRCA mutant cancer cells that gained resistance to genotoxic chemotherapy often displayed restored DNA repair by HR and/or restored fork protection (FP) implicating that the therapy was tolerated when DSB repair was intact or DSBs were prevented. Despite this well-supported paradigm that has been the impetus for targeted cancer therapy, here we argue that the toxic DNA lesion conferring response is instead single stranded DNA (ssDNA) gaps. We discuss the evidence that persistent ssDNA gaps formed in the wake of DNA replication rather than DSBs are responsible for cell killing following treatment with genotoxic chemotherapeutic agents. We also highlight that proteins, such as BRCA1, BRCA2, and RAD51 known for canonical DSB repair also have critical roles in normal replication as well as replication gap suppression (RGS) and repair. We review the literature that supports the idea that widespread gap induction proximal to treatment triggers apoptosis in a process that does not need or stem from DSB induction. Lastly, we discuss the clinical evidence for gaps and how to exploit them to enhance genotoxic chemotherapy response.en_US
dc.language.isoenen_US
dc.relation.ispartofDNA Repairen_US
dc.relation.urlhttps://doi.org/10.1016/j.dnarep.2021.103209en_US
dc.rightsCopyright © 2021. Published by Elsevier B.V.en_US
dc.subjectBRCA-RAD51 pathwayen_US
dc.subjectFork protectionen_US
dc.subjectHomologous recombinationen_US
dc.subjectReplication gap suppressionen_US
dc.subjectReplication stressen_US
dc.subjectSingle stranded DNAen_US
dc.titleRevisiting the BRCA-pathway through the lens of replication gap suppression: "Gaps determine therapy response in BRCA mutant cancer"en_US
dc.typeJournal Articleen_US
dc.source.journaltitleDNA repair
dc.source.volume107
dc.source.beginpage103209
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryNetherlands
dc.identifier.journalDNA repair
dc.contributor.departmentMolecular, Cell and Cancer Biologyen_US


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