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Cell Death and Differentiation

Cell Death and Differentiation

IF: 15.4
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Deubiquitinase OTUD6A promotes breast cancer progression by increasing TopBP1 stability and rendering tumor cells resistant to DNA-damaging therapy.

Published:29 June 2022 DOI: 10.1038/s41418-022-01036-6 PMID: 35768646
Yan Zhao, Xinping Huang, Dan Zhu, Min Wei, Jiechen Luo, Shuyu Yu, Yonglu Tian, Xiaofeng Zheng

Abstract

The DNA damage response (DDR) is critical for maintaining cellular homeostasis and genome integrity. Mounting evidence has shown that posttranslational protein modifications play vital roles in the DDR. In this study, we showed that deubiquitinase OTUD6A is involved in the DDR and is important for maintaining genomic stability. Mechanistically, in response to DNA damage, the abundance of OTUD6A was increased; meanwhile, PP2A interacted with OTUD6A and dephosphorylated OTUD6A at sites S70/71/74, which promoted nuclear localization of OTUD6A. Subsequently, OTUD6A was recruited to the damage site, where it interacted with TopBP1 and blocked the interaction between TopBP1 and its ubiquitin E3 ligase UBR5, decreasing K48-linked polyubiquitination and increasing the stability of TopBP1. OTUD6A depletion impaired CHK1 S345 phosphorylation and blocked cell cycle progression under DNA replication stress. Consistently, knockout of OTUD6A rendered mice hypersensitive to irradiation, shortened survival, and inhibited tumor growth by regulating TopBP1 in xenografted nude mice. Moreover, OTUD6A is expressed at high levels in breast cancer, and OTUD6A overexpression promotes cell proliferation, migration and invasion, indicating that dysregulation of OTUD6A expression contributes to genomic instability and is associated with tumor development. In summary, this study demonstrates that OTUD6A plays a critical role in promoting tumor cell resistance to chemoradiotherapy by deubiquitinating and stabilizing TopBP1.

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Procduct Name CAS Molecular Formula Supplier Price
MG-132 133407-82-6 C26H41N3O5 427 suppliers $11.00-$9807.90
MG-132 133407-82-6 C26H41N3O5 427 suppliers $11.00-$9807.90
MG-132 133407-82-6 C26H41N3O5 427 suppliers $11.00-$9807.90
MG-132 133407-82-6 C26H41N3O5 427 suppliers $11.00-$9807.90

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