AIMP2/p38, the scaffold for the multi-tRNA synthetase complex, responds to genotoxic stresses via p53.
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.
Han
Jung Min
JM
Center for Medicinal Protein Network and Systems Biology, College of Pharmacy, and College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea.
Park
Bum-Joon
BJ
Park
Sang Gyu
SG
Oh
Young Sun
YS
Choi
So Jung
SJ
Lee
Sang Won
SW
Hwang
Soon-Kyung
SK
Chang
Seung-Hee
SH
Cho
Myung-Haing
MH
Kim
Sunghoon
S
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
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