@article{17bcf261bea54e1aa546e99aafbb2f3c,
title = "DNA-PKcs-PIDDosome: A Nuclear Caspase-2-Activating Complex with Role in G2/M Checkpoint Maintenance",
abstract = "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 γ-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.",
keywords = "CELLCYCLE, DNA, SIGNALING",
author = "Mingan Shi and Vivian, {Carolyn J.} and Lee, {Kyung Jong} and Chunmin Ge and Keiko Morotomi-Yano and Claudia Manzl and Florian Bock and Shigeo Sato and Chieri Tomomori-Sato and Ruihong Zhu and Haug, {Jeffrey S.} and Swanson, {Selene K.} and Washburn, {Michael P.} and Chen, {David J.} and Chen, {Benjamin P C} and Andreas Villunger and Laurence Florens and Chunying Du",
note = "Funding Information: We thank J.W. Conaway, J.D. Robertson, and L. Wang for critical reading, and J.L. Workman, H. Yu, S. Lin, and L. Li for helpful discussions of the manuscript. We also thank K.M. Delventhal for caspase-2 mutagenesis; K.P. Smith, M.E. Peterson, A.G. Perera, and K. Staehling-Hampton for DNA sequencing; and J. Wunderlich for flow cytometry analyses. We are grateful to J. Yuan for the primary caspase-2 WT and deficient MEFs. We thank X. Wang for the pcDNA 3.1-caspase-2 construct, T.W. Mak for RAIDD-knockout MEFs, T. Kitamura for the Plat E packaging cells, and B. Vogelstein for the HCT116-p53+/+ and HCT116-p53−/− cells. We also thank members of the Du lab for helpful discussions. C.D. is supported by the Stowers Institute for Medical Research, D.J.C. by NIH grants CA50519 and PO1-CA92584, A.V. by Austrian Science Fund (FWF) project Y212B13 (START) and EU-RTN FP07—Apoptrain, and C.M. by the Tyrolean Science Fund (TWF).",
year = "2009",
month = feb,
day = "6",
doi = "10.1016/j.cell.2008.12.021",
language = "English (US)",
volume = "136",
pages = "508--520",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}