Journal
EMBO JOURNAL
Volume 21, Issue 12, Pages 3000-3008Publisher
OXFORD UNIV PRESS
DOI: 10.1093/emboj/cdf307
Keywords
apoptosis; DNA damage; DNA-dependent protein kinase; p53; Ser15
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Funding
- NCI NIH HHS [R01 CA050519, R37 CA050519] Funding Source: Medline
- NIA NIH HHS [AG 50519, AG 17709] Funding Source: Medline
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Mouse embryo fibroblasts (MEFs) expressing the adenovirus E1A protein undergo apoptosis upon exposure to ionizing radiation. We show here that immediately following gamma-irradiation, latent p53 formed a complex with the catalytic subunit of the DNA-dependent protein kinase (DNA-PKCS). The complex formation was DNase sensitive, suggesting that the proteins came together on the DNA, conceivably at strand breaks. This association was accompanied by phosphorylation of pre-existing, latent p53 at Ser18 (corresponding to Ser15 in human p53), which was not found in DNA-PKCS-/- cells. Most significantly, DNA damage-induced apoptosis was abolished in boil DNA-PKCS-/- and p53(-/-) cells. In addition, blocking synthesis of inducible p53 by cycloheximide did not abrogate apoptosis, suggesting that the latent population of p53 is sufficient for executing the apoptotic program. Finally, E1A-expressing MEFs from a p53 'knock-in' mouse where Ser18 was mutated to an alanine had an attenuated apoptotic response, indicating that phosphorylation of this site by DNA-PK is a contributing factor for apoptosis.
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