HDMX folds the nascent p53 mRNA following activation by the ATM kinase

Laurence Malbert-Colas; Anand Ponnuswamy; Vanesa Olivares-Illana; Anne-Sophie Tournillon; Nadia Naski; Robin Fåhraeus

doi:10.1016/j.molcel.2014.02.035

HDMX folds the nascent p53 mRNA following activation by the ATM kinase

Mol Cell. 2014 May 8;54(3):500-11. doi: 10.1016/j.molcel.2014.02.035.

Authors

Laurence Malbert-Colas¹, Anand Ponnuswamy², Vanesa Olivares-Illana³, Anne-Sophie Tournillon¹, Nadia Naski¹, Robin Fåhraeus⁴

Affiliations

¹ 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.
² 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.
³ Instituto de Fisica, Universidad Autonoma de San Luis Potosí, 78290 San Luis Potosí, Mexico.
⁴ 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. Electronic address: [email protected].

PMID: 24813712
DOI: 10.1016/j.molcel.2014.02.035

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Ataxia Telangiectasia Mutated Proteins / metabolism*
Base Sequence
Cell Cycle Proteins
DNA Damage
Gene Expression Regulation
Humans
Inverted Repeat Sequences
Molecular Sequence Data
Nuclear Proteins / chemistry
Nuclear Proteins / physiology*
Phosphorylation
Protein Binding
Protein Biosynthesis
Protein Processing, Post-Translational
Protein Structure, Tertiary
Proto-Oncogene Proteins / chemistry
Proto-Oncogene Proteins / physiology*
Proto-Oncogene Proteins c-mdm2 / metabolism
RNA Folding
RNA Processing, Post-Transcriptional
RNA, Messenger / chemistry
RNA, Messenger / genetics*
RNA, Messenger / metabolism
Sf9 Cells
Spodoptera
Substrate Specificity
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism

Substances

Cell Cycle Proteins
MDM4 protein, human
Nuclear Proteins
Proto-Oncogene Proteins
RNA, Messenger
TP53 protein, human
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
ATM protein, human
Ataxia Telangiectasia Mutated Proteins