DNA-PK suppresses a p53-independent apoptotic response to DNA damage

EMBO Reports
Kay E GurleyChristopher J Kemp

Abstract

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.

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Jan 14, 2009·Nucleic Acids Research·Tej K Pandita, Christine Richardson
Apr 9, 2013·Future Oncology·Christopher J Kemp, Carla Grandori
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Related Concepts

Genotoxic Stress
Receptor Down-Regulation
Protein p53
Apoptosis, Intrinsic Pathway
Mice, Knockout
DNA-dependent protein kinase
DNA
DNA Damage
DNA Repair
Intestines

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