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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Zhu M,Zhao H,Liao J,Xu X

doi

10.1093/nar/gku978

subject

Has Abstract

pub_date

2014-12-01 00:00:00

pages

13074-81

issue

21

eissn

0305-1048

issn

1362-4962

pii

gku978

journal_volume

42

pub_type

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