USP1 deubiquitinates PARP1 to regulate its trapping and PARylation activity

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2024-11-13 DOI:10.1126/sciadv.adp6567

Anna Nespolo, Linda Stefenatti, Ilenia Pellarin, Alice Gambelli, Gian Luca Rampioni Vinciguerra, Javad Karimbayli, Sara Barozzi, Fabrizio Orsenigo, Riccardo Spizzo, Milena S. Nicoloso, Ilenia Segatto, Sara D’Andrea, Michele Bartoletti, Emilio Lucia, Giorgio Giorda, Vincenzo Canzonieri, Fabio Puglisi, Barbara Belletti, Monica Schiappacassi, Gustavo Baldassarre, Maura Sonego

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引用次数: 0

Abstract

PARP inhibitors (PARPi) represent a game-changing treatment for patients with ovarian cancer with tumors deficient for the homologous recombination (HR) pathway treated with platinum (Pt)–based therapy. PARPi exert their cytotoxic effect by both trapping PARP1 on the damaged DNA and by restraining its enzymatic activity (PARylation). How PARP1 is recruited and trapped at the DNA damage sites and how resistance to PARPi could be overcome are still matters of investigation. Here, we described PARP1 as a substrate of the deubiquitinase USP1. At molecular level, USP1 binds PARP1 to remove its K63-linked polyubiquitination and controls PARP1 chromatin trapping and PARylation activity, regulating sensitivity to PARPi. In both Pt/PARPi-sensitive and -resistant cells, USP1/PARP1 combined blockade enhances replicative stress, DNA damage, and cell death. Our work dissected the biological interaction between USP1 and PARP1 and recommended this axis as a promising and powerful therapeutic choice for not only sensitive but also chemoresistant patients with ovarian cancer irrespective of their HR status.

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USP1 去泛素化 PARP1 以调节其捕获和 PARylation 活性

PARP抑制剂（PARPi）是一种改变卵巢癌患者治疗方法的药物，这些患者的肿瘤缺乏同源重组（HR）途径，并接受以铂（Pt）为基础的治疗。PARPi 通过将 PARP1 诱捕到受损 DNA 上并抑制其酶活性（PARylation）来发挥细胞毒性作用。PARP1 是如何被招募并被困在 DNA 损伤位点上的，以及如何克服 PARPi 的抗药性仍是研究的重点。在这里，我们将 PARP1 描述为去泛素化酶 USP1 的底物。在分子水平上，USP1结合PARP1以去除其K63连接的多泛素化，并控制PARP1的染色质捕获和PAR化活性，从而调节对PARPi的敏感性。在对 Pt/PARPi 敏感和耐受的细胞中，USP1/PARP1 联合阻断会增强复制应激、DNA 损伤和细胞死亡。我们的研究剖析了 USP1 和 PARP1 之间的生物相互作用，并建议将这一轴心作为一种有前途的、强有力的治疗选择，不仅适用于敏感的卵巢癌患者，也适用于化疗耐药的卵巢癌患者，无论其 HR 状态如何。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.