AIMP2/p38, the scaffold for the multi-tRNA synthetase complex, responds to genotoxic stresses via p53

Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11206-11. doi: 10.1073/pnas.0800297105. Epub 2008 Aug 11.

Abstract

AIMP2/p38 is a scaffolding protein required for the assembly of the macromolecular tRNA synthetase complex. Here, we describe a previously unknown function for AIMP2 as a positive regulator of p53 in response to genotoxic stresses. Depletion of AIMP2 increased resistance to DNA damage-induced apoptosis, and introduction of AIMP2 into AIMP2-deficient cells restored the susceptibility to apoptosis. Upon DNA damage, AIMP2 was phosphorylated, dissociated from the multi-tRNA synthetase complex, and translocated into the nuclei of cells. AIMP2 directly interacts with p53, thereby preventing MDM2-mediated ubiquitination and degradation of p53. Mutations in AIMP2, affecting its interaction with p53, hampered its ability to activate p53. Nutlin-3 recovered the level of p53 and the susceptibility to UV-induced cell death in AIMP2-deficient cells. This work demonstrates that AIMP2, a component of the translational machinery, functions as proapoptotic factor via p53 in response to DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / genetics
  • Active Transport, Cell Nucleus / radiation effects
  • Amino Acyl-tRNA Synthetases / genetics
  • Amino Acyl-tRNA Synthetases / metabolism*
  • Animals
  • Apoptosis / genetics
  • Apoptosis / radiation effects
  • Cell Line, Tumor
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • DNA Damage / drug effects
  • DNA Damage / genetics
  • DNA Damage / radiation effects*
  • Imidazoles / pharmacology
  • Mice
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Mutation
  • Phosphorylation / drug effects
  • Phosphorylation / radiation effects
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitination / drug effects
  • Ubiquitination / genetics
  • Ubiquitination / radiation effects
  • Ultraviolet Rays*

Substances

  • Imidazoles
  • Multiprotein Complexes
  • Piperazines
  • Tumor Suppressor Protein p53
  • aminoacyl-tRNA synthetase-associated protein p38
  • nutlin 3
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • Amino Acyl-tRNA Synthetases