DNA Damage-Induced Phosphorylation of p53 Alleviates Inhibition by MDM2

TLDR

DNA‑damaging agents signal to p53 through as yet unidentified post‑transcriptional mechanisms. The study aims to elucidate how DNA‑PK modulates p53 induction in response to DNA damage. The authors propose that DNA‑PK phosphorylates p53 at serines 15 and 37, thereby modulating its activity. Phosphorylation of p53 at serines 15 and 37 after DNA damage reduces its interaction with MDM2 and impairs MDM2‑mediated inhibition of p53 transactivation, likely via a conformational change.

Abstract

DNA-damaging agents signal to p53 through as yet unidentified posttranscriptional mechanisms. Here we show that phosphorylation of human p53 at serine 15 occurs after DNA damage and that this leads to reduced interaction of p53 with its negative regulator, the oncoprotein MDM2, in vivo and in vitro. Furthermore, using purified DNA-dependent protein kinase (DNA-PK), we demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of MDM2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by DNA-PK (or other protein kinases with similar specificity) in response to DNA damage.