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DNA‐PK suppresses a p53‐independent apoptotic response to DNA damage
Author(s) -
Gurley Kay E,
Moser Russell,
Gu Yansong,
Hasty Paul,
Kemp Christopher J
Publication year - 2009
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2008.214
Subject(s) - dna damage , apoptosis , biology , dna repair , ku80 , microbiology and biotechnology , ku70 , dna pkcs , dna ligase , chek1 , dna , checkpoint kinase 2 , cancer research , cell cycle , cell cycle checkpoint , biochemistry , dna binding protein , gene , transcription factor
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.