USP7 counteracts SCFbetaTrCP- but not APCCdh1-mediated proteolysis of Claspin
Research output: Contribution to journal › Journal article › Research › peer-review
Claspin is an adaptor protein that facilitates the ataxia telangiectasia and Rad3-related (ATR)-mediated phosphorylation and activation of Chk1, a key effector kinase in the DNA damage response. Efficient termination of Chk1 signaling in mitosis and during checkpoint recovery requires SCF(betaTrCP)-dependent destruction of Claspin. Here, we identify the deubiquitylating enzyme ubiquitin-specific protease 7 (USP7) as a novel regulator of Claspin stability. Claspin and USP7 interact in vivo, and USP7 is required to maintain steady-state levels of Claspin. Furthermore, USP7-mediated deubiquitylation markedly prolongs the half-life of Claspin, which in turn increases the magnitude and duration of Chk1 phosphorylation in response to genotoxic stress. Finally, we find that in addition to the M phase-specific, SCF(betaTrCP)-mediated degradation, Claspin is destabilized by the anaphase-promoting complex (APC) and thus remains unstable in G1. Importantly, we demonstrate that USP7 specifically opposes the SCF(betaTrCP)- but not APC(Cdh1)-mediated degradation of Claspin. Thus, Claspin turnover is controlled by multiple ubiquitylation and deubiquitylation activities, which together provide a flexible means to regulate the ATR-Chk1 pathway.
Original language | English |
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Journal | Journal of Cell Biology |
Volume | 184 |
Issue number | 1 |
Pages (from-to) | 13-9 |
Number of pages | 6 |
ISSN | 0021-9525 |
DOIs | |
Publication status | Published - 2009 |
Externally published | Yes |
Bibliographical note
Keywords: Adaptor Proteins, Signal Transducing; Cell Line; DNA Damage; G1 Phase; Humans; Phosphorylation; Protein Kinases; SKP Cullin F-Box Protein Ligases; Substrate Specificity; Ubiquitin Thiolesterase; Ubiquitin-Protein Ligase Complexes; Ubiquitination
ID: 18698031