Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies

• Published in: Nature communications Vol. 7; no. 1; p. 12425
• Main Authors: Ding, Xia, Chaudhuri, Arnab Ray, Callen, Elsa, Pang, Yan, Biswas, Kajal, Klarmann, Kimberly D., Martin, Betty K., Burkett, Sandra, Cleveland, Linda, Stauffer, Stacey, Sullivan, Teresa, Dewan, Aashish, Marks, Hanna, Tubbs, Anthony T., Wong, Nancy, Buehler, Eugen, Akagi, Keiko, Martin, Scott E., Keller, Jonathan R., Nussenzweig, André, Sharan, Shyam K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.08.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/106; 13/89; 14; 631/208/68; 631/337/1427/2190; 631/67/68; 64; 64/60; 692/4028/67/1059/2326; 82; 82/1; Animals; BRCA2 Protein - deficiency; BRCA2 Protein - metabolism; Cancer; Cell cycle; Cell Survival - drug effects; Cloning; DNA Replication - drug effects; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Homologous Recombination - drug effects; Humanities and Social Sciences; Humans; Integrases - metabolism; Medical research; Mice; Models, Biological; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - drug effects; Mouse Embryonic Stem Cells - metabolism; MRE11 Homologue Protein - metabolism; multidisciplinary; Mutation; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - deficiency; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Proteins; Science; Science (multidisciplinary); Stem cells; Toxicity; Tumors; United States > US
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12425

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 Brca2 cko/ko mouse embryonic stem cells (mESCs), carrying a null ( ko ) and a conditional ( cko ) allele of Brca2 , results in viable Brca2 ko/ko cells. PARP1 deficiency does not restore HR in Brca2 ko/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 Brca2 cko/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. The PARP inhibitor olaparib is an approved treatment method for women with BRCA1 and BRCA2 mutation associated cancers. Here the authors show that olaparib can contribute to synthetic viability of cells if PARP1 is inhibited before BRCA2 loss.