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Nucleic Acids Res. 2014 Dec 1;42(21):13110-21. doi: 10.1093/nar/gku1034. Epub 2014 Oct 29.

HERC2-USP20 axis regulates DNA damage checkpoint through Claspin.

Author information

1
Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China Key Laboratory of Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China lou.zhenkun@mayo.edu.
2
Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China Key Laboratory of Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.
3
Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA.
4
Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China Key Laboratory of Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA.
5
Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA lou.zhenkun@mayo.edu.

Abstract

The DNA damage response triggers cell-cycle checkpoints, DNA repair and apoptosis using multiple post-translational modifications as molecular switches. However, how ubiquitination regulates ATR signaling in response to replication stress and single-strand break is still unclear. Here, we identified the deubiquitination enzyme (DUB) USP20 as a pivotal regulator of ATR-related DDR pathway. Through screening a panel of DUBs, we identified USP20 as critical for replication stress response. USP20 is phosphorylated by ATR, resulting in disassociation of the E3 ubiquitin ligase HERC2 from USP20 and USP20 stabilization. USP20 in turn deubiquitinates and stabilizes Claspin and enhances the activation of ATR-Chk1 signaling. These findings reveal USP20 to be a novel regulator of ATR-dependent DNA damage signaling.

PMID:
25355518
PMCID:
PMC4245938
DOI:
10.1093/nar/gku1034
[Indexed for MEDLINE]
Free PMC Article

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