The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin.
The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin.
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DOI：
10.1038/s41556-021-00807-6
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发表时间：
2022-01
影响因子：
21.3
通讯作者：
Lord CJ
中科院分区：
文献类型：
--
作者：
Krastev DB;Li S;Sun Y;Wicks AJ;Hoslett G;Weekes D;Badder LM;Knight EG;Marlow R;Pardo MC;Yu L;Talele TT;Bartek J;Choudhary JS;Pommier Y;Pettitt SJ;Tutt ANJ;Ramadan K;Lord CJ
聚（adp -核糖）聚合酶（PARP）抑制剂通过将PARP1捕获在染色质结合状态来诱导同源重组缺陷癌症的抗肿瘤活性。细胞如何处理捕获的PARP1仍不清楚。利用野生型和捕获缺陷型PARP1突变体，结合内源性蛋白的快速免疫沉淀质谱和Apex2接近标记，我们描绘了捕获和非捕获PARP1的基于质谱的相互作用组。这些分析确定了捕获的PARP1和泛素调节的p97 atp酶/分离酶之间的相互作用。我们发现，在捕获后，PARP1被PIAS4 sumy化，随后被sumo靶向的E3泛素连接酶RNF4泛素化，这些事件促进了p97的募集和被捕获的PARP1从染色质上去除。小分子p97复合物抑制剂，包括临床使用的药物双硫仑（CuET）的代谢物，延长PARP1捕获时间，增强PARP抑制剂诱导的同源重组缺陷肿瘤细胞和患者来源的肿瘤类器官的细胞毒性。总之，这些结果表明p97 atp酶在捕获PARP1的加工和肿瘤细胞对PARP抑制剂的反应中起着关键作用。Krastev等人报道，被捕获的PARP1经历SUMOylation，随后泛素化，导致p97 atp酶的募集，从染色质上去除被捕获的PARP1，并防止PARP抑制剂诱导的细胞毒性。
Poly (ADP-ribose) polymerase (PARP) inhibitors elicit antitumour activity in homologous recombination-defective cancers by trapping PARP1 in a chromatin-bound state. How cells process trapped PARP1 remains unclear. Using wild-type and a trapping-deficient PARP1 mutant combined with rapid immunoprecipitation mass spectrometry of endogenous proteins and Apex2 proximity labelling, we delineated mass spectrometry-based interactomes of trapped and non-trapped PARP1. These analyses identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase/segregase. We found that following trapping, PARP1 is SUMOylated by PIAS4 and subsequently ubiquitylated by the SUMO-targeted E3 ubiquitin ligase RNF4, events that promote recruitment of p97 and removal of trapped PARP1 from chromatin. Small-molecule p97-complex inhibitors, including a metabolite of the clinically used drug disulfiram (CuET), prolonged PARP1 trapping and enhanced PARP inhibitor-induced cytotoxicity in homologous recombination-defective tumour cells and patient-derived tumour organoids. Together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 and the response of tumour cells to PARP inhibitors. Krastev et al. report that trapped PARP1 undergoes SUMOylation, followed by ubiquitylation, resulting in the recruitment of the p97 ATPase to remove trapped PARP1 from chromatin and prevent PARP inhibitor-induced cytotoxicity.
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