TRIM21 suppresses CHK1 activation by preferentially targeting CLASPIN for K63-linked ubiquitination
Xuefei Zhu, Jingwei Xue, Xing Jiang, Yamin Gong, Congwen Gao, Ting Cao, Qian Li, Lulu Bai, Yuwei Li, Gaixia Xu, Bin Peng, Xingzhi Xu
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.