ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair Journal Article

   


Authors: Chen, C. C.; Kass, E. M.; Yen, W. F.; Ludwig, T.; Moynahan, M. E.; Chaudhuri, J.; Jasin, M.
Article Title: ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair
Abstract: BRCA1 is essential for homology-directed repair (HDR) of DNA double-strand breaks in part through antagonism of the nonhomologous end-joining factor 53BP1. The ATM kinase is involved in various aspects of DNA damage signaling and repair, but how ATM participates in HDR and genetically interacts with BRCA1 in this process is unclear. To investigate this question, we used the Brca1S1598F mouse model carrying a mutation in the BRCA1 C-terminal domain of BRCA1. Whereas ATM loss leads to a mild HDR defect in adult somatic cells, we find that ATM inhibition leads to severely reduced HDR in Brca1S1598F cells. Consistent with a critical role for ATM in HDR in this background, loss of ATM leads to synthetic lethality of Brca1S1598F mice. Whereas both ATM and BRCA1 promote end resection, which can be regulated by 53BP1, 53bp1 deletion does not rescue the HDR defects of Atm mutant cells, in contrast to Brca1 mutant cells. These results demonstrate that ATM has a role in HDR independent of the BRCA1-53BP1 antagonism and that its HDR function can become critical in certain contexts. © 2017, National Academy of Sciences. All rights reserved.
Keywords: homologous recombination; brca1; olaparib; atm; homology-directed repair
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 114
Issue: 29
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2017-07-18
Start Page: 7665
End Page: 7670
Language: English
DOI: 10.1073/pnas.1706392114
PROVIDER: scopus
PMCID: PMC5530697
PUBMED: 28659469
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85024404385&doi=10.1073%2fpnas.1706392114&partnerID=40&md5=c05d9c77f59cba16be70404977b9617c
Notes: Article -- Export Date: 2 August 2017 -- Source: Scopus
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MSK Authors
  1. Mary Ellen Moynahan
    105 Moynahan
  2. Maria Jasin
    249 Jasin
  3. Jayanta Chaudhuri
    71 Chaudhuri
  4. Elizabeth M Kass
    13 Kass
  5. Wei-Feng Yen
    13 Yen
  6. Chun-Chin Chen
    6 Chen
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