Unknown

Dataset Information

0

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.

SUBMITTER: Ding X 

PROVIDER: S-EPMC4979061 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications


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), ca  ...[more]

Similar Datasets

| S-EPMC5540764 | biostudies-literature
| S-EPMC5584172 | biostudies-literature
| S-EPMC4177344 | biostudies-literature
| S-EPMC4747901 | biostudies-other
2020-03-24 | GSE147468 | GEO
| S-EPMC5575319 | biostudies-literature
| S-EPMC5608777 | biostudies-literature
2017-07-21 | PXD007078 | Pride
| S-EPMC7418109 | biostudies-literature
| S-EPMC7455564 | biostudies-literature