Dissecting The Genetic Interaction Of Brca1 And Atm In Homology-Directed Dna Repair

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Abstract
Homology-directed repair (HDR) plays a crucial role in the repair of DNA double-strand breaks. Defects in genes involved in HDR compromise genome integrity and predispose cells to tumorigenesis. The breast tumor suppressor BRCA1 is essential for HDR in part through antagonizing the nonhomologous end joining factor 53BP1. The ATM kinase is involved in various aspects of DNA damage signaling. Both BRCA1 and ATM have functions in the early steps of HDR, however their epistatic relationship is largely unclear. In this study we address how mutations in BRCA1 affect its genetic interaction with ATM and 53BP1 in HDR. In a Brca1 S1598F mouse model carrying a mutation in the phosphoprotein-binding BRCT domain at the C terminus, ATM becomes critical to support HDR and this regulation is independent of the BRCA1-53BP1 antagonism. Deficiency of ATM leads to synthetic lethality in the Brca1 S1598F mutant mice associated with severely compromised HDR. On the other hand, in a Brca1 ex11 mutant expressing the BRCA1 ?11 splicing isoform lacking the central region, whether ATM supports HDR is modulated by the status of 53BP1: Only in the absence of 53BP1 does ATM promote HDR. These results suggest that mutations in the BRCT domain and the exon 11-encoding region of BRCA1 differentially affect how ATM kinase participates in HDR. Importantly, while normally not essential, ATM could be critical for HDR proficiency in certain contexts of BRCA1 deficiency, providing a new perspective for targeting BRCA1 mutant tumors.
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2018
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53BP1; ATM; BRCA1; Homologous recombination; Homology-directed repair; Olaparib
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Cell & Developmental Biology
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Doctor of Philosophy
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Government Document
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Attribution-NonCommercial-NoDerivatives 4.0 International
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dissertation or thesis
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