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.
Highlights
(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations
Effects of PARP inhibitor (PARPi) are not limited to homologous recombination (HR)-deficient cells, as treatment of HR-proficient cells with different doses of olaparib resulted in suppression of CHK1 activation in response to replicative stress (Supplementary Fig. 1a), as reported previously[19]
To determine whether Poly (ADP-ribose) polymerase (PARP) inhibition or PARP1 deficiency affected recruitment of MRE11 to stalled replication forks, we examined the presence of MRE11 at the fork in mouse embryonic stem cells (mESCs) treated with HU (4 mM, 4 h) or HU with olaparib (1 mM, 2 h pretreatment followed by HU combination for another 4 h) by iPOND28
Summary
(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations. It is well established that BRCA1 and BRCA2 function as tumour suppressors by maintaining genomic integrity Both proteins are required for the repair of double-strand breaks (DSBs) by homologous recombination (HR) and for the stability of stalled replication forks[1,2,3]. Their role in HR has been utilized to develop a therapeutic strategy that is based on the synthetic lethality of BRCA-deficient tumour by poly (ADP-ribose) polymerase (PARP or ADP-ribosyltransferase diphtheria toxin-like, ARTD) inhibitors[4,5,6,7]. PARP1 deficiency suppressed the recruitment of MRE11 nuclease to stalled replication fork, which contributed to fork protection in cells lacking BRCA2
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