Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance

Abstract

BRCA1 plays a critical role in homology-directed repair (HDR) of DNA double strand breaks, and the repair defect of BRCA1-mutant cancer cells is being targeted with platinum drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. We have employed relatively simple and sensitive assays to determine the function of BRCA1 variants or mutants in two HDR mechanisms, homologous recombination (HR) and single strand annealing (SSA), and in conferring resistance to cisplatin and olaparib in human cancer cells. Our results define the functionality of the top 22 patient-derived BRCA1 missense variants and the contribution of different domains of BRCA1 and its E3 ubiquitin ligase activity to HDR and drug resistance. Importantly, our results also demonstrate that the BRCA1-PALB2 interaction dictates the choice between HR and SSA. These studies establish functional and mutational landscapes of BRCA1 for HDR and therapy resistance, while revealing novel insights into BRCA1 regulatory mechanisms and HDR pathway choice.

Article and author information

Author details

  1. Rachel W Anantha

    Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Srilatha Simhadri

    Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Tzeh Keong Foo

    Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0168-7054
  4. Susanna Miao

    Department of Genetics, School of Arts and Sciences, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jingmei Liu

    Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Zhiyuan Shen

    Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2834-0309
  7. Shridar Ganesan

    Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Bing Xia

    Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    For correspondence
    xiabi@cinj.rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3259-6139

Funding

National Cancer Institute (R01CA138804)

  • Bing Xia

Congressionally Directed Medical Research Programs (W81XWH-10-1-0486)

  • Rachel W Anantha

National Cancer Institute (R01CA188096)

  • Bing Xia

National Cancer Institute (R01CA169182)

  • Shridar Ganesan

National Cancer Institute (R01CA195612)

  • Zhiyuan Shen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2017, Anantha et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Rachel W Anantha
  2. Srilatha Simhadri
  3. Tzeh Keong Foo
  4. Susanna Miao
  5. Jingmei Liu
  6. Zhiyuan Shen
  7. Shridar Ganesan
  8. Bing Xia
(2017)
Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance
eLife 6:e21350.
https://doi.org/10.7554/eLife.21350

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https://doi.org/10.7554/eLife.21350