Document Detail

Phosphorylation-triggered CUEDC2 degradation promotes UV-induced G1 arrest through APC/C(Cdh1) regulation.
MedLine Citation:
PMID:  23776205     Owner:  NLM     Status:  MEDLINE    
DNA damage triggers cell cycle arrest to provide a time window for DNA repair. Failure of arrest could lead to genomic instability and tumorigenesis. DNA damage-induced G1 arrest is generally achieved by the accumulation of Cyclin-dependent kinase inhibitor 1 (p21). However, p21 is degraded and does not play a role in UV-induced G1 arrest. The mechanism of UV-induced G1 arrest thus remains elusive. Here, we have identified a critical role for CUE domain-containing protein 2 (CUEDC2) in this process. CUEDC2 binds to and inhibits anaphase-promoting complex/cyclosome-Cdh1 (APC/C(Cdh1)), a critical ubiquitin ligase in G1 phase, thereby stabilizing Cyclin A and promoting G1-S transition. In response to UV irradiation, CUEDC2 undergoes ERK1/2-dependent phosphorylation and ubiquitin-dependent degradation, leading to APC/C(Cdh1)-mediated Cyclin A destruction, Cyclin-dependent kinase 2 inactivation, and G1 arrest. A nonphosphorylatable CUEDC2 mutant is resistant to UV-induced degradation. Expression of this stable mutant effectively overrides UV-induced G1-S block. These results establish CUEDC2 as an APC/C(Cdh1) inhibitor and indicate that regulated CUEDC2 degradation is critical for UV-induced G1 arrest.
Wei-Na Zhang; Jie Zhou; Tao Zhou; Ai-Ling Li; Na Wang; Jin-Jing Xu; Yan Chang; Jiang-Hong Man; Xin Pan; Tao Li; Wei-Hua Li; Rui Mu; Bing Liang; Liang Chen; Bao-Feng Jin; Qing Xia; Wei-Li Gong; Xue-Min Zhang; Li Wang; Hui-Yan Li
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-06-17
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  110     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-07-03     Completed Date:  2013-09-26     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  11017-22     Citation Subset:  IM    
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MeSH Terms
Anaphase-Promoting Complex-Cyclosome
Carrier Proteins / antagonists & inhibitors,  genetics,  metabolism*
Cell Line, Tumor
Cyclin A / metabolism
Cyclin-Dependent Kinase 2 / metabolism
G1 Phase Cell Cycle Checkpoints / genetics,  physiology*,  radiation effects
HEK293 Cells
HeLa Cells
MAP Kinase Signaling System / genetics
Membrane Proteins / antagonists & inhibitors,  genetics,  metabolism*
Mutagenesis, Site-Directed
Phosphorylation / genetics
Ubiquitin-Protein Ligase Complexes / genetics,  metabolism*
Ultraviolet Rays
Reg. No./Substance:
0/CUEDC2 protein, human; 0/Carrier Proteins; 0/Cyclin A; 0/Membrane Proteins; EC protein, human; EC Kinase 2; EC Complex-Cyclosome; EC Ligase Complexes

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