Ali Ambereen, Zhang Ji, Bao Shideng, Liu Irene, Otterness Diane, Dean Nicholas M, Abraham Robert T, Wang Xiao-Fan
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Genes Dev. 2004 Feb 1;18(3):249-54. doi: 10.1101/gad.1176004.
The checkpoint kinase ATM is centrally involved in the cellular response to DNA double-strand breaks. However, the mechanism of ATM activation during genotoxic stress is only partially understood. Here we report a direct regulatory linkage between the protein serine-threonine phosphatase 5 (PP5) and ATM. PP5 interacts with ATM in a DNA-damage-inducible manner. Reduced expression of PP5 attenuated DNA-damage-induced activation of ATM. Expression of a catalytically inactive PP5 mutant inhibited the phosphorylation of ATM substrates and the autophosphorylation of ATM on Ser 1981, and caused an S-phase checkpoint defect in DNA-damaged cells. Together our findings indicate that PP5 plays an essential role in the activation and checkpoint signaling functions of ATM in cells that have suffered DNA double-strand breaks.
检查点激酶ATM在细胞对DNA双链断裂的反应中起核心作用。然而,基因毒性应激期间ATM激活的机制仅得到部分理解。在此我们报告蛋白丝氨酸 - 苏氨酸磷酸酶5(PP5)与ATM之间存在直接的调控联系。PP5以DNA损伤诱导的方式与ATM相互作用。PP5表达降低减弱了DNA损伤诱导的ATM激活。催化失活的PP5突变体的表达抑制了ATM底物的磷酸化以及ATM在丝氨酸1981位点的自磷酸化,并在DNA损伤的细胞中导致S期检查点缺陷。我们的研究结果共同表明,PP5在遭受DNA双链断裂的细胞中ATM的激活和检查点信号传导功能中起重要作用。