Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510-8034, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510-8034, USA.
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510-8034, USA.
Structure. 2024 Nov 7;32(11):2083-2093.e5. doi: 10.1016/j.str.2024.09.006. Epub 2024 Oct 14.
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.
聚（ADP-核糖）糖水解酶（PARG）抑制剂目前正在临床开发用于治疗 DNA 修复缺陷型癌症；然而，其确切的作用机制仍不清楚。在这里，我们报告 PARG 抑制导致过多的 PAR 化聚（ADP-核糖）聚合酶 1（PARP1），从而降低 PARP1 正确定位于 DNA 损伤部位的能力。引人注目的是，定位错误的 PARP1 会在整个核内积聚成聚集体。PARP1 的催化活性被阻断可防止聚集体形成，表明 PAR 链在这个过程中起着关键作用。最后，我们发现 PARP1 核聚集体具有高度持久性，并与细胞质 PARP1 的裂解片段相关，最终导致细胞死亡。总的来说，我们的数据揭示了 PARG 抑制剂细胞毒性的一种意外机制，这将为这些药物作为抗癌治疗药物的应用提供启示。
