DNA-PKcs-PIDDosome: A Nuclear Caspase-2-Activating Complex with Role in G2/M Checkpoint Maintenance

Mingan Shi, Carolyn J. Vivian, Kyung Jong Lee, Chunmin Ge, Keiko Morotomi-Yano, Claudia Manzl, Florian Bock, Shigeo Sato, Chieri Tomomori-Sato, Ruihong Zhu, Jeffrey S. Haug, Selene K. Swanson, Michael P. Washburn, David J. Chen, Benjamin P C Chen, Andreas Villunger, Laurence Florens, Chunying Du

Research output: Contribution to journalArticle

74 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)508-520
Number of pages13
JournalCell
Volume136
Issue number3
DOIs
StatePublished - Feb 6 2009

Keywords

  • CELLCYCLE
  • DNA
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Shi, M., Vivian, C. J., Lee, K. J., Ge, C., Morotomi-Yano, K., Manzl, C., Bock, F., Sato, S., Tomomori-Sato, C., Zhu, R., Haug, J. S., Swanson, S. K., Washburn, M. P., Chen, D. J., Chen, B. P. C., Villunger, A., Florens, L., & Du, C. (2009). DNA-PKcs-PIDDosome: A Nuclear Caspase-2-Activating Complex with Role in G2/M Checkpoint Maintenance. Cell, 136(3), 508-520. https://doi.org/10.1016/j.cell.2008.12.021