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

Xuefei Zhu1,2, Jingwei Xue1, Xing Jiang1

  • 1Guangdong Key Laboratory for Genome Stability & Disease Prevention and Carson International Cancer Center and Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China.

Nucleic Acids Research
|January 20, 2022
PubMed

Insights

The E3 ligase TRIM21 targets CLASPIN, suppressing CHK1 activation and promoting cancer. This discovery reveals TRIM21 as a potential therapeutic target for cancer treatment.

Area of Science:

  • Molecular biology
  • Cancer research
  • Ubiquitination pathways

Background:

  • Increased expression of E3 ligase TRIM21 is observed across various cancers.
  • The specific molecular pathways targeted by TRIM21 overexpression are not well understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which TRIM21 overexpression contributes to tumorigenesis.
  • To identify the functional targets of TRIM21 in cancer cells.

Main Methods:

  • Co-immunoprecipitation assays to demonstrate TRIM21-CLASPIN interaction.
  • In vitro ubiquitination assays to analyze ubiquitination patterns.
  • Analysis of CHK1 activation, replication fork stability, and tumorigenesis in response to TRIM21 modulation.

Main Results:

  • TRIM21 directly interacts with and ubiquitinates CLASPIN, a key mediator of ATR-dependent CHK1 activation.
  • TRIM21-mediated K63-linked ubiquitination of CLASPIN inhibits its K6-linked ubiquitination, crucial for TIPIN interaction and chromatin loading.
  • TRIM21 overexpression, unlike a catalytically inactive mutant, impairs CHK1 activation, destabilizes replication forks, and promotes tumorigenesis.

Conclusions:

  • TRIM21 suppresses CHK1 activation by promoting K63-linked ubiquitination of CLASPIN.
  • This mechanism highlights TRIM21 as a potential therapeutic target for various cancers.

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