DNA-PK suppresses a p53-independent apoptotic response to DNA damage.
p53 is required for DNA damage-induced apoptosis, which is central to its function as a tumour suppressor. Here, we show that the apoptotic defect of p53-deficient cells is nearly completely rescued by inactivation of any of the three subunits of the DNA repair holoenzyme DNA-dependent protein kinase (DNA-PK). Intestinal crypt cells from p53 nullizygous mice were resistant to radiation-induced apoptosis, whereas apoptosis in DNA-PK(cs)/p53, Ku80/p53 and Ku70/p53 double-null mice was quantitatively equivalent to that seen in wild-type mice. This p53-independent apoptotic response was specific to the loss of DNA-PK, as it was not seen in ligase IV (Lig4)/p53 or ataxia telangiectasia mutated (Atm)/p53 double-null mice. Furthermore, it was associated with an increase in phospho-checkpoint kinase 2 (CHK2), and cleaved caspases 3 and 9, the latter indicating engagement of the intrinsic apoptotic pathway. This shows that there are two separate, but equally effective, apoptotic responses to DNA damage: one is p53 dependent and the other, engaged in the absence of DNA-PK, does not require p53.
Gurley
Kay E
KE
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Moser
Russell
R
Gu
Yansong
Y
Hasty
Paul
P
Kemp
Christopher J
CJ
D000818:Animals; D017209:Apoptosis; D004249:DNA Damage / Q000235:genetics*; D051747:DNA-Activated Protein Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D051379:Mice; D018345:Mice, Knockout; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D051747:DNA-Activated Protein Kinase