TRIM21 Suppresses CHK1 Activation by Preferentially Targeting CLASPIN for K63-linked Ubiquitination

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2022 Jan 20

PMID 35048968

Authors

Xuefei Zhu

Jingwei Xue

Xing Jiang

Yamin Gong

Congwen Gao

Ting Cao

Qian Li

Lulu Bai

Yuwei Li

Gaixia Xu

Bin Peng

Xingzhi Xu

Affiliations

Soon will be listed here.

Abstract

Expression of the E3 ligase TRIM21 is increased in a broad spectrum of cancers; however, the functionally relevant molecular pathway targeted by TRIM21 overexpression remains largely unknown. Here, we show that TRIM21 directly interacts with and ubiquitinates CLASPIN, a mediator for ATR-dependent CHK1 activation. TRIM21-mediated K63-linked ubiquitination of CLASPIN counteracts the K6-linked ubiquitination of CLASPIN which is essential for its interaction with TIPIN and subsequent chromatin loading. We further show that overexpression of TRIM21, but not a TRIM21 catalytically inactive mutant, compromises CHK1 activation, leading to replication fork instability and tumorigenesis. Our findings demonstrate that TRIM21 suppresses CHK1 activation by preferentially targeting CLASPIN for K63-linked ubiquitination, providing a potential target for cancer therapy.

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