USP22 Interacts with PALB2 and Promotes Chemotherapy Resistance via Homologous Recombination of DNA Double-Strand Breaks.
USP22 Interacts with PALB2 and Promotes Chemotherapy Resistance via Homologous Recombination of DNA Double-Strand Breaks.
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USP22与PALB2相互作用，并通过DNA双链断裂的同源重组来促进化学疗法抗性。
DOI：
10.1158/1541-7786.mcr-19-0053
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发表时间：
2020-03
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同源重组（Homologous recombination， HR）是一种高度保守的促进DNA双链断裂修复的途径。几种去泛素酶（DUBs）被认为是通过HR参与DNA损伤修复（DDR）的关键参与者。在这里，我们报道了在多种癌症类型中高度过表达的DUB USP22，它通过PALB2的c端WD40结构域与PALB2直接相互作用，是HR所必需的。这种相互作用在体外刺激USP22的催化活性。此外，我们发现USP22对于BRCA2、PALB2和Rad51向dsb募集是必要的，这部分是通过USP22稳定BRCA2和PALB2水平实现的。综上所述，我们的结果描述了USP22在DNA修复中的作用。这项研究为USP22过表达促进肺癌化疗耐药提供了新的和令人兴奋的机制见解。我们相信这项研究以及其他研究将有助于开发针对USP22和已知结合伙伴的靶向药物，用于肺癌治疗。
Homologous recombination (HR) is a highly conserved pathway that can facilitate the repair of DNA double-strand breaks (DSBs). Several Deubiquitinases (DUBs) have been implicated as key players in DNA damage repair (DDR) through HR. Here we report USP22, a DUB that is highly overexpressed in multiple cancer types, is necessary for HR through a direct interaction with PALB2 through its C-terminal WD40 domain. This interaction stimulates USP22 catalytic activity in-vitro. Furthermore, we show USP22 is necessary for BRCA2, PALB2, and Rad51 recruitment to DSBs and this is in part through USP22 stabilizing BRCA2 and PALB2 levels. Taken together, our results describe a role for USP22 in DNA repair. This research provides new and exciting mechanistic insights into how USP22 overexpression promotes chemo-resistance in lung cancer. We believe this study, and others, will help aid in developing targeted drugs towards USP22 and known binding partners for lung cancer treatment.