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Mol. Cell. Biol. doi:10.1128/MCB.01610-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Absence of Ser389 phosphorylation in p53 affects the basal gene-expression level of many p53-dependent genes and alters the biphasic response to UV exposure in MEFs

Laboratory of Toxicology, Pathology and Genetics (TOX), National Institute of Public Health and the Environment (RIVM), Bilthoven, the Netherlands; MicroArray Department & Integrative Bioinformatics Unit (MAD-IBU), Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam (UvA), Amsterdam, the Netherlands

^* To whom correspondence should be addressed. Email: Annemieke.de.Vries{at}rivm.nl.

	Abstract

Phosphorylation is important in p53-mediated DNA damage responses. After UV irradiation, p53 is phosphorylated specifically at murine residue Ser389. Phosphorylation mutant p53.S389A cells and mice show reduced apoptosis and compromised tumor suppression after UV. We investigated the underlying cellular processes by time-series analysis of UV-induced gene-expression responses in wild-type, p53.S389A, and p53^-/- MEFs. Absence of p53.S389 phosphorylation already causes small endogenous gene-expression changes for 2,253, mostly p53-dependent, genes. These showed basal gene-expression levels intermediate to wild-type and p53^-/-, possibly to readjust the p53 network. Overall, the p53.S389A mutation lifts p53-dependent gene repression similar to p53^-/-, but has lesser effect on p53-dependently induced genes.

In wild-type, 6,058 genes responded strictly biphasic to UV irradiation. The early stress response, 0-3 hours, results in activation of processes to prevent accumulation of DNA damage in cells, whereas the late response, 12-24 hours, relates more to re-entering the cell cycle. Although the p53.S389A UV gene response was only subtly changed, many cellular processes were significantly affected. The early response was affected the most, and many cellular processes were phase-specifically lost, gained or altered, e.g., ‘induction-of-apoptosis’, ‘cell-division’, and ‘DNA-repair’, respectively. Altogether, p53.S389 phosphorylation seems essential for many p53-target genes and p53-dependent processes.