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Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies

Author

Listed:
  • Xia Ding

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH)

  • Arnab Ray Chaudhuri

    (Laboratory of Genome Integrity, National Cancer Institute, NIH)

  • Elsa Callen

    (Laboratory of Genome Integrity, National Cancer Institute, NIH)

  • Yan Pang

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH)

  • Kajal Biswas

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH)

  • Kimberly D. Klarmann

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH
    Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research)

  • Betty K. Martin

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH
    Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research)

  • Sandra Burkett

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH)

  • Linda Cleveland

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH)

  • Stacey Stauffer

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH)

  • Teresa Sullivan

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH)

  • Aashish Dewan

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH)

  • Hanna Marks

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH)

  • Anthony T. Tubbs

    (Laboratory of Genome Integrity, National Cancer Institute, NIH)

  • Nancy Wong

    (Laboratory of Genome Integrity, National Cancer Institute, NIH)

  • Eugen Buehler

    (Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH)

  • Keiko Akagi

    (Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center)

  • Scott E. Martin

    (Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH
    Present address: Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA 94080, USA)

  • Jonathan R. Keller

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH
    Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research)

  • André Nussenzweig

    (Laboratory of Genome Integrity, National Cancer Institute, NIH)

  • Shyam K. Sharan

    (Mouse Cancer Genetics Program, National Cancer Institute, NIH)

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations. BRCA1- and BRCA2-mutated cells, which are homologous recombination (HR) deficient, are hypersensitive to PARPi through the mechanism of synthetic lethality. Here we examine the effect of PARPi on HR-proficient cells. Olaparib pretreatment, PARP1 knockdown or Parp1 heterozygosity of Brca2cko/ko mouse embryonic stem cells (mESCs), carrying a null (ko) and a conditional (cko) allele of Brca2, results in viable Brca2ko/ko cells. PARP1 deficiency does not restore HR in Brca2ko/ko cells, but protects stalled replication forks from MRE11-mediated degradation through its impaired recruitment. The functional consequence of Parp1 heterozygosity on BRCA2 loss is demonstrated by a significant increase in tumorigenesis in Brca2cko/cko mice. Thus, while olaparib efficiently kills BRCA2-deficient cells, we demonstrate that it can also contribute to the synthetic viability if PARP is inhibited before BRCA2 loss.

Suggested Citation

  • Xia Ding & Arnab Ray Chaudhuri & Elsa Callen & Yan Pang & Kajal Biswas & Kimberly D. Klarmann & Betty K. Martin & Sandra Burkett & Linda Cleveland & Stacey Stauffer & Teresa Sullivan & Aashish Dewan &, 2016. "Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12425
    DOI: 10.1038/ncomms12425
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