Li Ying, Mitsuhashi Shinya, Ikejo Makoto, Miura Nobuaki, Kawamura Takeshi, Hamakubo Takao, Ubukata Makoto
Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Kita-ku, Sapporo, Japan.
Biosci Biotechnol Biochem. 2012;76(3):486-94. doi: 10.1271/bbb.110774.
The optimal cellular responses to DNA damage are modulated by kinase and phosphatase. The ataxia telangiectasia mutated (ATM) is a Ser/Thr kinase which is the core of the DNA damage signaling apparatus. The Ser/Thr protein phosphatase type 1 (PP1) inhibitor, tautomycetin (TC) and an antibody to the phospho-(S/T)Q sites of the ATM substrate were used to identify the common substrates for PP1 and ATM in regulating the pathway for DNA damage response. Ribosomal protein S6 (RPS6) was first identified as a substrate for PP1 and ATM. The phosphorylation at Ser247 of RPS6 was then significantly decreased by PP1-mediated dephosphorylation immediately after UV irradiation. These results suggest that PP1 specifically dephosphorylated RPS6 at phospho-Ser247 in vivo. In response to DNA damage, ATM activity was finally required for the phosphorylation of RPS6 at Ser247. We propose from these results a novel mechanism for modulating the RPS6 function by PP1 and ATM which regulates cell growth and survival in response to DNA-damage stimuli.
激酶和磷酸酶可调节细胞对DNA损伤的最佳反应。共济失调毛细血管扩张症突变基因（ATM）是一种丝氨酸/苏氨酸激酶，是DNA损伤信号传导机制的核心。使用1型丝氨酸/苏氨酸蛋白磷酸酶（PP1）抑制剂互隔交链孢酚（TC）以及针对ATM底物磷酸化（丝氨酸/苏氨酸）谷氨酰胺位点的抗体，来鉴定PP1和ATM在调节DNA损伤反应途径中的共同底物。核糖体蛋白S6（RPS6）首先被鉴定为PP1和ATM的底物。紫外线照射后，PP1介导的去磷酸化作用使RPS6的丝氨酸247位点的磷酸化水平显著降低。这些结果表明，PP1在体内可特异性地使磷酸化丝氨酸247位点的RPS6去磷酸化。在DNA损伤反应中，最终需要ATM活性来使RPS6的丝氨酸247位点磷酸化。基于这些结果，我们提出了一种由PP1和ATM调节RPS6功能的新机制，该机制可响应DNA损伤刺激来调节细胞生长和存活。
