title: Phosphorylation-triggered CUEDC2 degradation promotes UV-induced G1 arrest through APC/C(Cdh1) regulation.
abstract: 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.
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.forename: Ai-Ling
authors.initials: AL
authors.lastname: Li
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.forename: Jin-Jing
authors.initials: JJ
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Chang
authors.forename: Jiang-Hong
authors.initials: JH
authors.lastname: Man
authors.forename: Xin
authors.initials: X
authors.lastname: Pan
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Mu
authors.forename: Bing
authors.initials: B
authors.lastname: Liang
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Bao-Feng
authors.initials: BF
authors.lastname: Jin
authors.forename: Qing
authors.initials: Q
authors.lastname: Xia
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Gong
authors.forename: Xue-Min
authors.initials: XM
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Hui-Yan
authors.initials: HY
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D064173:Anaphase-Promoting Complex-Cyclosome; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation / Q000235:genetics; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C519556:CUEDC2 protein, human; D002352:Carrier Proteins; D019925:Cyclin A; D008565:Membrane Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2