Poly (ADP-ribose) glycohydrolase (PARG) inhibitors are currently under clinical development for the treatment of DNA repair-deficient cancers; however, their precise mechanism of action is still unclear. Here, we report that PARG inhibition leads to excessive PARylated poly (ADP-ribose) polymerase 1 (PARP1) reducing the ability of PARP1 to properly localize to sites of DNA damage. Strikingly, the mis-localized PARP1 accumulates as aggregates throughout the nucleus. Abrogation of the catalytic activity of PARP1 prevents aggregate formation, indicating that PAR chains play a key role in this process. Finally, we find that PARP1 nuclear aggregates were highly persistent and were associated with cleaved cytoplasmic PARP1, ultimately leading to cell death. Overall, our data uncover an unexpected mechanism of PARG inhibitor cytotoxicity, which will shed light on the use of these drugs as anti-cancer therapeutics.

中文翻译：

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PARG 抑制诱导 PARylated PARP1 的核聚集


聚（ADP-核糖）糖水解酶 （PARG） 抑制剂目前正在临床开发中，用于治疗 DNA 修复缺陷型癌症;然而，它们的确切作用机制仍不清楚。在这里，我们报道了 PARG 抑制导致过量的 PARylated poly （ADP-ribose） 聚合酶 1 （PARP1），从而降低了 PARP1 正确定位到 DNA 损伤位点的能力。引人注目的是，错误定位的 PARP1 在整个细胞核中以聚集体的形式积累。PARP1 催化活性的消除会阻止聚集体的形成，表明 PAR 链在此过程中起关键作用。最后，我们发现 PARP1 核聚集体具有高度持久性，并且与裂解的细胞质 PARP1 相关，最终导致细胞死亡。总体而言，我们的数据揭示了 PARG 抑制剂细胞毒性的意想不到的机制，这将阐明这些药物作为抗癌疗法的使用。