Serine-Threonine Kinase 38 regulates CDC25A stability and the DNA damage-induced G2/M checkpoint
Serine-Threonine Kinase 38 regulates CDC25A stability and the DNA damage-induced G2/M checkpoint
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DOI：
10.1016/j.cellsig.2015.04.013
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发表时间：
2015-08-01
影响因子：
4.8
通讯作者：
Miyagawa, Kiyoshi
中科院分区：
文献类型：
--
作者：
Fukasawa, Takemichi;Enomoto, Atsushi;Miyagawa, Kiyoshi
细胞通过激活蛋白激酶介导的信号通路来响应DNA损伤，这些信号通路促进细胞周期停滞、DNA修复或凋亡。细胞周期停滞的关键调节因子是CDC 25 A（细胞分裂周期25同源物A）磷酸酶。CDC 25 A通常通过去磷酸化和激活细胞周期蛋白/细胞周期蛋白依赖性激酶（CDK）复合物在调节G1/S和G2/M转换中起关键作用;然而，CDC 25 A在响应DNA损伤时特异性降解。在这里，我们证明，丝氨酸-苏氨酸激酶38（STK 38）的耗尽防止DNA损伤诱导的降解的CDC 25 A和随后的G2期阻滞，STK 38直接磷酸化CDC 25 A在Ser-76，导致CDC 25 A的降解。综上所述，这些结果表明，STK 38介导的CDC 25 A在Ser-76的磷酸化和随后的CDC 25 A降解是促进DNA损伤诱导的G2/M检查点激活所必需的。(C)© 2015 Elsevier Inc版权所有。
Cells respond to DNA damage by activating protein kinase-mediated signaling pathways that promote cell-cycle arrest, DNA repair, or apoptosis. A key regulator of cell-cycle arrest is the CDC25A (cell division cycle 25 homologue A) phosphatase. CDC25A normally plays a pivotal role in regulating the G1/S and G2/M transitions by dephosphorylating and activating cyclin/cyclin-dependent kinase (CDK) complexes; however, CDC25A is specifically degraded in response to DNA damage. Here, we demonstrate that the depletion of serine-threonine kinase 38 (STK38) prevents the DNA-damage-induced degradation of CDC25A and subsequent G2 arrest, and that STK38 directly phosphorylates CDC25A at Ser-76, resulting in CDC25A's degradation. Taken together, these results indicate that the STK38-mediated phosphorylation of CDC25A at Ser-76 and the subsequent degradation of CDC25A are required to promote DNA damage-induced G2/M checkpoint activation. (C) 2015 Elsevier Inc All rights reserved.