Phosphorylation-triggered CUEDC2 degradation promotes UV-induced G1 arrest through APC/CCdh1 regulation
Phosphorylation-triggered CUEDC2 degradation promotes UV-induced G1 arrest through APC/CCdh1 regulation
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DOI：
10.1073/pnas.1221009110
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发表时间：
2013-07-02
影响因子：
11.1
通讯作者：
Li, Hui-Yan
中科院分区：
文献类型：
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作者：
Zhang, Wei-Na;Zhou, Jie;Li, Hui-Yan
DNA损伤触发细胞周期阻滞，为DNA修复提供时间窗口。抑制失败可能导致基因组不稳定和肿瘤发生。DNA损伤诱导的G(1)阻滞通常是通过细胞周期蛋白依赖性激酶抑制剂1的积累来实现的（p21）。然而，p21被降解，在紫外线诱导的G(1)阻滞中不起作用。因此，紫外线诱导的G(1)阻滞的机制尚不清楚。在这里，我们已经确定了含CUE结构域蛋白2 （CUEDC2）在这一过程中的关键作用。CUEDC2结合并抑制G(1)期关键的泛素连接酶——促后期复合物/环体- cdh1 (APC/C-Cdh1)，从而稳定Cyclin a，促进G(1)-S转变。在紫外线照射下，CUEDC2经历erk1 /2依赖性磷酸化和泛素依赖性降解，导致APC/ c - cdh1介导的细胞周期蛋白A破坏、细胞周期蛋白依赖性激酶2失活和G(1)阻滞。一个不可磷酸化的CUEDC2突变体对紫外线诱导的降解具有抗性。该稳定突变体的表达有效地覆盖了紫外线诱导的G(1)-S块。这些结果表明CUEDC2是APC/C-Cdh1抑制剂，并表明CUEDC2的降解对紫外线诱导的G(1)阻滞至关重要。
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.