title: Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress.
abstract: Aminoacyl-tRNA synthetases (ARSs) acylate transfer (t)RNAs with amino acids. Charging tRNAs with the right amino acids is the first step in translation; therefore, the accurate and error-free functioning of ARSs is an essential prerequisite for translational fidelity. A recent study found that methionine (Met) can be incorporated into non-Met residues of proteins through methionylation of non-cognate tRNAs under conditions of oxidative stress. However, it was not understood how this mis-methionylation is achieved. Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins. The expression of a mutant MRS containing the substitutions S209D and S825D, mimicking dual phosphorylation, reduced ROS levels and cell death. This controlled inaccuracy of MRS seems to serve as a defense mechanism against ROS-mediated damage at the cost of translational fidelity.
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Dae Gyu
authors.initials: DG
authors.lastname: Kim
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Byung-Gyu
authors.initials: BG
authors.lastname: Kim
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Yang
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jeena
authors.initials: J
authors.lastname: Hong
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Taehee
authors.initials: T
authors.lastname: Kang
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Oh
authors.affiliation: Research Institute of Pharmaceutical Sciences, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Kyung Rok
authors.initials: KR
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Byung Woo
authors.initials: BW
authors.lastname: Han
authors.affiliation: Department of Molecular Bioscience, Kang Won National University, Chuncheon-si, Gangwon-do 200-701, Korea.
authors.forename: Byung Joon
authors.initials: BJ
authors.lastname: Hwang
authors.affiliation: School of Life Science and Biotechnology, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Beom Sik
authors.initials: BS
authors.lastname: Kang
authors.affiliation: Department of Computer Science and Engineering Center for Computer Graphics and Virtual Reality, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Kang
authors.affiliation: Department of Computer Science and Engineering Center for Computer Graphics and Virtual Reality, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea nanarom1@snu.ac.kr sungkim@snu.ac.kr.
authors.forename: Nam Hoon
authors.initials: NH
authors.lastname: Kwon
authors.affiliation: Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Suwon 443-270, Korea nanarom1@snu.ac.kr sungkim@snu.ac.kr.
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
mesh_terms: D000215:Acylation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008718:Methionine-tRNA Ligase / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D012343:RNA, Transfer; D008718:Methionine-tRNA Ligase
keywords: Cell protection; ERK; Methionyl-tRNA synthetase; Misacylation; Reactive oxygen species
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