title: Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies.
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 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.
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.
authors: Xia
authors: X
authors: Ding
authors: Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20893, USA.
authors: Arnab
authors: A
authors: Ray Chaudhuri
authors: Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20893, USA.
authors: Elsa
authors: E
authors: Callen
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.
authors: Yan
authors: Y
authors: Pang
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.
authors: Kajal
authors: K
authors: Biswas
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.|Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Kimberly D
authors: KD
authors: Klarmann
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.|Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Betty K
authors: BK
authors: Martin
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.
authors: Sandra
authors: S
authors: Burkett
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.
authors: Linda
authors: L
authors: Cleveland
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.
authors: Stacey
authors: S
authors: Stauffer
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.
authors: Teresa
authors: T
authors: Sullivan
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.
authors: Aashish
authors: A
authors: Dewan
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.
authors: Hanna
authors: H
authors: Marks
authors: Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20893, USA.
authors: Anthony T
authors: AT
authors: Tubbs
authors: Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20893, USA.
authors: Nancy
authors: N
authors: Wong
authors: Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors: Eugen
authors: 0000-0001-7167-676X
authors: E
authors: Buehler
authors: Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors: Keiko
authors: K
authors: Akagi
authors: Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
authors: Scott E
authors: SE
authors: Martin
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.|Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Jonathan R
authors: JR
authors: Keller
authors: Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20893, USA.
authors: André
authors: A
authors: Nussenzweig
authors: Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.
authors: Shyam K
authors: SK
authors: Sharan
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000172:deficiency* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D019426:Integrases / Q000378:metabolism; D000076228:MRE11 Homologue Protein / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology
chemical_list: D024682:BRCA2 Protein; C106711:BRCA2 protein, mouse; C512689:Mre11a protein, mouse; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; C045073:Cre recombinase; D019426:Integrases; D000076228:MRE11 Homologue Protein