DNA-PKcs-PIDDosome: a nuclear caspase-2-activating complex with role in G2/M checkpoint maintenance.
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.
Shi
Mingan
M
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Vivian
Carolyn J
CJ
Lee
Kyung-Jong
KJ
Ge
Chunmin
C
Morotomi-Yano
Keiko
K
Manzl
Claudia
C
Bock
Florian
F
Sato
Shigeo
S
Tomomori-Sato
Chieri
C
Zhu
Ruihong
R
Haug
Jeffrey S
JS
Swanson
Selene K
SK
Washburn
Michael P
MP
Chen
David J
DJ
Chen
Benjamin P C
BP
Villunger
Andreas
A
Florens
Laurence
L
Du
Chunying
C
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D053143:Caspase 2 / Q000737:chemistry / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D053418:Death Domain Receptor Signaling Adaptor Proteins; D005347:Fibroblasts / Q000378:metabolism; D005720:Gamma Rays; D006801:Humans; D051379:Mice; D008938:Mitosis; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D016415:Sequence Alignment
D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D009687:Nuclear Proteins; C485896:PIDD1 protein, human; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases