In:
Nucleic Acids Research, Oxford University Press (OUP), Vol. 50, No. 3 ( 2022-02-22), p. 1517-1530
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.
Type of Medium:
Online Resource
ISSN:
0305-1048
,
1362-4962
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2022
detail.hit.zdb_id:
1472175-2
SSG:
12
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