Department of Molecular Pharmacology and Experimental Therapeutics, Radiation Oncology, and Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3406-11. doi: 10.1073/pnas.1013715108. Epub 2011 Feb 7.
Poly(ADP-ribose) polymerase (PARP) inhibitors are strikingly toxic to cells with defects in homologous recombination (HR). The mechanistic basis for these findings is incompletely understood. Here, we show that PARP inhibitor treatment induces phosphorylation of DNA-dependent protein kinase substrates and stimulates error-prone nonhomologous end joining (NHEJ) selectively in HR-deficient cells. Notably, inhibiting DNA-dependent protein kinase activity reverses the genomic instability previously reported in these cells after PARP inhibition. Moreover, disabling NHEJ by using genetic or pharmacologic approaches rescues the lethality of PARP inhibition or down-regulation in cell lines lacking BRCA2, BRCA1, or ATM. Collectively, our results not only implicate PARP1 catalytic activity in the regulation of NHEJ in HR-deficient cells, but also indicate that deregulated NHEJ plays a major role in generating the genomic instability and cytotoxicity in HR-deficient cells treated with PARP inhibitors.
聚（ADP-核糖）聚合酶（PARP）抑制剂对同源重组（HR）缺陷的细胞具有显著的毒性。这些发现的机制基础尚未完全理解。在这里，我们表明 PARP 抑制剂处理诱导 DNA 依赖性蛋白激酶底物的磷酸化，并选择性地刺激 HR 缺陷细胞中易错的非同源末端连接（NHEJ）。值得注意的是，抑制 DNA 依赖性蛋白激酶活性可逆转之前报道的这些细胞在 PARP 抑制后出现的基因组不稳定性。此外，通过使用遗传或药理学方法抑制 NHEJ，可挽救 BRCA2、BRCA1 或 ATM 缺失的细胞系中 PARP 抑制或下调的致死性。总之，我们的结果不仅表明 PARP1 催化活性参与了 HR 缺陷细胞中 NHEJ 的调节，还表明在 PARP 抑制剂处理的 HR 缺陷细胞中，失调的 NHEJ 在产生基因组不稳定性和细胞毒性方面发挥着重要作用。
