Regulated protein synthesis via changes in mRNA structures forms an important part of how prokaryotic cells adapt protein expression in response to changes in the environment. Little is known regarding how this concept has adapted to regulate mRNA translation via signaling pathways in mammalian cells. Here, we show that following phosphorylation by the ataxia telangiectasia mutated (ATM) kinase at serine 403, the C-terminal RING domain of HDMX binds the nascent p53 mRNA to promote a conformation that supports the p53 mRNA-HDM2 interaction and the induction of p53 synthesis. HDMX and its homolog HDM2 bind the same p53 internal ribosome entry sequences (IRES) structure but with different specificity and function. The results show how HDMX and HDM2 act as nonredundant IRES trans-acting factors (ITAFs) to bring a positive synergistic effect on p53 expression during genotoxic stress by first altering the structure of the newly synthesized p53 mRNA followed by stimulation of translation.

Cibles Thérapeutiques Equipe Labellisée Ligue Contre le Cancer INSERM Unité 940 Institut de Génétique Moléculaire Université Paris 7 Hôpital St Louis 27 rue Juliette Dodu 75010 Paris France

Cibles Thérapeutiques Equipe Labellisée Ligue Contre le Cancer INSERM Unité 940 Institut de Génétique Moléculaire Université Paris 7 Hôpital St Louis 27 rue Juliette Dodu 75010 Paris France; RECAMO Masaryk Memorial Cancer Institute Zluty kopec 7 656 53 Brno Czech Republic

Instituto de Fisica Universidad Autonoma de San Luis Potosí 78290 San Luis Potosí Mexico

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