HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability.

Abstract	CLASPIN is an essential mediator in the DNA replication checkpoint, responsible for ATR (ataxia telangiectasia and Rad3-related protein)-dependent activation of CHK1 (checkpoint kinase 1). Here we found a dynamic signaling pathway that regulates CLASPIN turn over. Under unperturbed conditions, the E3 ubiquitin ligase HERC2 regulates the stability of the deubiquitinating enzyme USP20 by promoting ubiquitination-mediated proteasomal degradation. Under replication stress, ATR-mediated phosphorylation of USP20 results in the disassociation of HERC2 from USP20. USP20 in turn deubiquitinates K48-linked-polyubiquitinated CLASPIN, stabilizing CLASPIN and ultimately promoting CHK1 phosphorylation and CHK1-directed checkpoint activation. Inhibition of USP20 expression promotes chromosome instability and xenograft tumor growth. Taken together, our findings demonstrated a novel function of HERC2/USP20 in coordinating CHK1 activation by modulating CLASPIN stability, which ultimately promotes genome stability and suppresses tumor growth.
Authors	Min Zhu, Hongchang Zhao, Ji Liao, Xingzhi Xu
Journal	Nucleic acids research (Nucleic Acids Res) Vol. 42 Issue 21 Pg. 13074-81 (Dec 01 2014) ISSN: 1362-4962 [Electronic] England
PMID	25326330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
Chemical References	Adaptor Proteins, Signal Transducing CLSPN protein, human Guanine Nucleotide Exchange Factors USP20 protein, human HERC2 protein, human Ubiquitin-Protein Ligases Protein Kinases ATR protein, human Ataxia Telangiectasia Mutated Proteins CHEK1 protein, human Checkpoint Kinase 1 Chek1 protein, mouse Ubiquitin Thiolesterase
Topics	Adaptor Proteins, Signal Transducing (metabolism) Animals Ataxia Telangiectasia Mutated Proteins (metabolism) Cell Line, Tumor Checkpoint Kinase 1 DNA Replication Enzyme Activation Female Guanine Nucleotide Exchange Factors (metabolism) HEK293 Cells Humans Mice, Inbred BALB C Mice, Nude Neoplasms (pathology) Phosphorylation Protein Kinases (metabolism) Protein Stability Stress, Physiological Ubiquitin Thiolesterase (metabolism) Ubiquitin-Protein Ligases Ultraviolet Rays

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