Phosphorylation-triggered CUEDC2 degradation promotes UV-induced G₁ arrest through APC/CCᵈʰ¹ regulation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-07, Vol.110 (27), p.11017-11022
• Main Authors: Zhang, Wei-Na, Zhou, Jie, Zhou, Tao, Li, Ai-Ling, Wang, Na, Xu, Jin-Jing, Chang, Yan, Man, Jiang-Hong, Pan, Xin, Li, Tao, Li, Weihua, Rui, Mu, Liang, Bing, Ma, Yukun, Jin, Bao-Feng, Xia, Qing, Gong, Wei-Li, Zhang, Xue-Min, Wang, Li, Li, Hui-Yan
• Format: Article
• Language: English
• Subjects: Biological Sciences; carcinogenesis; cell cycle checkpoints; cyclin-dependent kinase; cyclins; DNA; DNA damage; DNA repair; mutants; phosphorylation; ubiquitin-protein ligase; ultraviolet radiation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1221009110

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 G ₁ 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 G ₁ arrest. The mechanism of UV-induced G ₁ 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 G ₁ phase, thereby stabilizing Cyclin A and promoting G ₁–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 G ₁ arrest. A nonphosphorylatable CUEDC2 mutant is resistant to UV-induced degradation. Expression of this stable mutant effectively overrides UV-induced G ₁–S block. These results establish CUEDC2 as an APC/C Cᵈʰ¹ inhibitor and indicate that regulated CUEDC2 degradation is critical for UV-induced G ₁ arrest.