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TRIM21 suppresses CHK1 activation by preferentially targeting CLASPIN for K63-linked ubiquitination.

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.

SUBMITTER: Zhu X

PROVIDER: S-EPMC8860585 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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TRIM21 suppresses CHK1 activation by preferentially targeting CLASPIN for K63-linked ubiquitination.

Zhu Xuefei X Xue Jingwei J Jiang Xing X Gong Yamin Y Gao Congwen C Cao Ting T Li Qian Q Bai Lulu L Li Yuwei Y Xu Gaixia G Peng Bin B Xu Xingzhi X

Nucleic acids research 20220201 3

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 loadi ...[more]

PMID: 35048968

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