The Institute for Cancer Studies, Department of Oncology, Faculty of Medicine Dentistry and Health Sciences, University of Sheffield, Sheffield, UK.
Cell Cycle. 2012 Mar 1;11(5):990-7. doi: 10.4161/cc.11.5.19482.
Poly(ADP-ribose) glycohydrolase (PARG), removes poly(ADP-ribose) subunits from proteins that have previously been modified by poly(ADP-ribose) polymerse. This ensures that modification is transient, and it is suggested that removal of poly(ADP-ribose) is essential for some types of DNA repair. Here we show increased γH2AX foci formation and increased homologous recombination when PARG is inhibited. These effects are reduced when replication is inhibited, suggesting that in the absence of PARG activity, replication forks collapse, and homologous recombination is induced for repair. Consistent with this, we show that cells deficient in the homologous recombination protein BRCA2 are sensitive to PARG depletion or inhibition. These data raise the exciting possibility that PARG inhibitors may be used to specifically kill BRCA2 and other homologous recombination-deficient tumors.
聚（ADP-核糖）糖水解酶（PARG）从先前被聚（ADP-核糖）聚合酶修饰的蛋白质上去除聚（ADP-核糖）亚单位。这确保了修饰是短暂的，并且有人认为聚（ADP-核糖）的去除对于某些类型的 DNA 修复是必不可少的。在这里，我们显示当 PARG 被抑制时，γH2AX 焦点形成增加和同源重组增加。当复制被抑制时，这些效应降低，这表明在缺乏 PARG 活性的情况下，复制叉崩溃，并且诱导同源重组进行修复。与此一致，我们表明同源重组蛋白 BRCA2 缺陷的细胞对 PARG 耗尽或抑制敏感。这些数据提出了一个令人兴奋的可能性，即 PARG 抑制剂可用于特异性杀死 BRCA2 和其他同源重组缺陷型肿瘤。
