Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.
Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20893, USA.
Nat Commun. 2016 Aug 8;7:12425. 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.
聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）奥拉帕尼已被批准用于治疗与 BRCA1 和 BRCA2 突变相关的晚期卵巢癌。BRCA1 和 BRCA2 突变的细胞同源重组（HR）缺陷，通过合成致死的机制对 PARPi 高度敏感。在这里，我们研究了 PARPi 对 HR 有效的细胞的影响。奥拉帕尼预处理、PARP1 敲低或携带 BRCA2 缺失（ko）和条件性（cko）等位基因的 Brca2(cko/ko) 小鼠胚胎干细胞（mESCs）中的 Parp1 杂合性导致具有生存能力的 Brca2(ko/ko) 细胞。PARP1 缺陷不能恢复 Brca2(ko/ko) 细胞中的 HR，但通过其受损募集来保护停滞的复制叉免受 MRE11 介导的降解。Parp1 杂合性对 BRCA2 缺失的功能后果通过 Brca2(cko/cko) 小鼠中肿瘤形成的显著增加得到证明。因此，虽然奥拉帕尼能有效地杀死 BRCA2 缺陷细胞，但我们证明，如果在 BRCA2 缺失之前抑制 PARP，它也可以有助于合成存活。
