Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies

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, Hanna Marks, Anthony T. Tubbs, Nancy Wong, Eugen Buehler, Keiko Akagi, Scott E. Martin, Jonathan R. Keller, André Nussenzweig () and Shyam K. Sharan ()
Additional contact information
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
Betty K. Martin: Mouse Cancer Genetics Program, National Cancer Institute, NIH
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
Jonathan R. Keller: Mouse Cancer Genetics Program, National Cancer Institute, NIH
André Nussenzweig: Laboratory of Genome Integrity, National Cancer Institute, NIH
Shyam K. Sharan: Mouse Cancer Genetics Program, National Cancer Institute, NIH

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12425

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