title: AIMP2/p38, the scaffold for the multi-tRNA synthetase complex, responds to genotoxic stresses via p53.
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.
authors.affiliation: Center for Medicinal Protein Network and Systems Biology, College of Pharmacy, and College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Han
authors.forename: Bum-Joon
authors.initials: BJ
authors.lastname: Park
authors.forename: Sang Gyu
authors.initials: SG
authors.lastname: Park
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Oh
authors.forename: So Jung
authors.initials: SJ
authors.lastname: Choi
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Soon-Kyung
authors.initials: SK
authors.lastname: Hwang
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Chang
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D007093:Imidazoles; D046912:Multiprotein Complexes; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C474321:aminoacyl-tRNA synthetase-associated protein p38; C482205:nutlin 3; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D000604:Amino Acyl-tRNA Synthetases