Inhibition of poly(ADP-ribose) glycohydrolase (PARG) specifically kills BRCA2-deficient tumor cells
Inhibition of poly(ADP-ribose) glycohydrolase (PARG) specifically kills BRCA2-deficient tumor cells
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DOI：
10.4161/cc.11.5.19482
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发表时间：
2012-03-01
期刊：
影响因子：
4.3
通讯作者：
Bryant, Helen E.
中科院分区：
文献类型：
--
作者：
Fathers, Catherine;Drayton, Ross M.;Bryant, Helen E.
聚（ADP-核糖）糖水解酶（PARG）从先前已被聚（ADP-核糖）聚合酶修饰的蛋白质中去除聚（ADP-核糖）亚基。这确保了修饰是瞬时的，并且表明去除聚（ADP-核糖）对于某些类型的DNA修复是必不可少的。在这里，我们发现增加γ H2 AX灶形成和增加同源重组时，PARG被抑制。当复制被抑制时，这些作用降低，表明在PARG活性不存在的情况下，复制叉崩溃，并诱导同源重组进行修复。与此一致，我们表明同源重组蛋白BRCA 2缺陷的细胞对PARG耗竭或抑制敏感。这些数据提出了令人兴奋的可能性，PARG抑制剂可用于特异性杀死BRCA 2和其他同源重组缺陷型肿瘤。
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 gamma H2AX 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.