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DNA damage‐induced apoptosis requires the DNA‐dependent protein kinase, and is mediated by the latent population of p53
Author(s) -
Woo Richard A.,
Jack Melissa T.,
Xu Yang,
Burma Sandeep,
Chen David J.,
Lee Patrick W.K.
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdf307
Subject(s) - library science , population , national laboratory , gerontology , biology , environmental ethics , medicine , demography , sociology , engineering , philosophy , engineering physics , computer science
Mouse embryo fibroblasts (MEFs) expressing the adenovirus E1A protein undergo apoptosis upon exposure to ionizing radiation. We show here that immediately following γ‐irradiation, latent p53 formed a complex with the catalytic subunit of the DNA‐dependent protein kinase (DNA‐PK CS ). 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‐PK CS −/− cells. Most significantly, DNA damage‐induced apoptosis was abolished in both DNA‐PK CS −/− 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.