Open AccessTRIM21 suppresses CHK1 activation by preferentially targeting CLASPIN for K63-linked ubiquitination
Author(s) -
Xuefei Zhu,
Jianru Xue,
Xingyu Jiang,
Yamin Gong,
Gao Chang-yuan,
Ting Cao,
Qian Li,
Lulu Bai,
Yuwei Li,
Gaixia Xu,
Bin Peng,
Xingzhi Xu
Publication year - 2022
Publication title -
nucleic acids research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.008
H-Index - 537
eISSN - 1362-4954
pISSN - 0305-1048
DOI - 10.1093/nar/gkac011
Subject(s) - ubiquitin , ubiquitin ligase , biology , cancer research , microbiology and biotechnology , carcinogenesis , hek 293 cells , timeless , mutant , genetics , cancer , neuroscience , cell culture , gene , circadian rhythm
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.