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    Revisiting the BRCA-pathway through the lens of replication gap suppression: "Gaps determine therapy response in BRCA mutant cancer"

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    Authors
    Cantor, Sharon B
    UMass Chan Affiliations
    Molecular, Cell and Cancer Biology
    Document Type
    Journal Article
    Publication Date
    2021-08-13
    Keywords
    BRCA-RAD51 pathway
    Fork protection
    Homologous recombination
    Replication gap suppression
    Replication stress
    Single stranded DNA
    
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    Link to Full Text
    https://doi.org/10.1016/j.dnarep.2021.103209
    Abstract
    The 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.
    Source
    Cantor 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.
    DOI
    10.1016/j.dnarep.2021.103209
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/51810
    PubMed ID
    34419699
    Rights
    Copyright © 2021. Published by Elsevier B.V.
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.dnarep.2021.103209
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