Shi Mingan, Vivian Carolyn J, Lee Kyung-Jong, Ge Chunmin, Morotomi-Yano Keiko, Manzl Claudia, Bock Florian, Sato Shigeo, Tomomori-Sato Chieri, Zhu Ruihong, Haug Jeffrey S, Swanson Selene K, Washburn Michael P, Chen David J, Chen Benjamin P C, Villunger Andreas, Florens Laurence, Du Chunying
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Cell. 2009 Feb 6;136(3):508-20. doi: 10.1016/j.cell.2008.12.021.
Caspase-2 is unique among all the mammalian caspases in that it is the only caspase that is present constitutively in the cell nucleus, in addition to other cellular compartments. However, the functional significance of this nuclear localization is unknown. Here we show that DNA damage induced by gamma-radiation triggers the phosphorylation of nuclear caspase-2 at the S122 site within its prodomain, leading to its cleavage and activation. This phosphorylation is carried out by the nuclear serine/threonine protein kinase DNA-PKcs and promoted by the p53-inducible death-domain-containing protein PIDD within a large nuclear protein complex consisting of DNA-PKcs, PIDD, and caspase-2, which we have named the DNA-PKcs-PIDDosome. This phosphorylation and the catalytic activity of caspase-2 are involved in the maintenance of a G2/M DNA damage checkpoint and DNA repair mediated by the nonhomologous end-joining (NHEJ) pathway. The DNA-PKcs-PIDDosome thus represents a protein complex that impacts mammalian G2/M DNA damage checkpoint and NHEJ.
半胱天冬酶 -2在所有哺乳动物半胱天冬酶中是独特的，因为它是唯一除了存在于其他细胞区室之外，还组成性地存在于细胞核中的半胱天冬酶。然而，这种核定位的功能意义尚不清楚。在这里，我们表明，γ辐射诱导的DNA损伤触发了细胞核中半胱天冬酶 -2前结构域内S122位点的磷酸化，导致其切割和激活。这种磷酸化由核丝氨酸/苏氨酸蛋白激酶DNA-PKcs进行，并由p53诱导的含死亡结构域蛋白PIDD在由DNA-PKcs、PIDD和半胱天冬酶 -2组成的大型核蛋白复合物中促进，我们将其命名为DNA-PKcs-PIDDosome。这种磷酸化和半胱天冬酶 -2的催化活性参与了G2/M期DNA损伤检查点的维持以及由非同源末端连接（NHEJ）途径介导的DNA修复。因此，DNA-PKcs-PIDDosome代表了一种影响哺乳动物G2/M期DNA损伤检查点和NHEJ的蛋白复合物。
