Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival
Name
Samson-2010-Human AlkB homolog.pdf
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2.04 MB
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Author(s)
Fu, Dragony
Brophy, Jennifer Ann
Atmore, Kyle Aaquil
Begley, Ulrike
Begley, Thomas J.
Paules, Richard S.
Chan, Clement T. Y.
Dedon, Peter C
Samson, Leona D
Date Issued
March 2010
Journal
Molecular and Cellular Biology
Publisher
American Society for Microbiology
Citation
Fu, D. et al. “Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival.” Molecular and Cellular Biology 30 (2010): 2449-2459. Web. 2 Nov. 2011. © 2010 American Society for Microbiology
Version
Author's final manuscript
Abstract
tRNA nucleosides are extensively modified to ensure their proper function in translation. However, many of the enzymes responsible for tRNA modifications in mammals await identification. Here, we show that human AlkB homolog 8 (ABH8) catalyzes tRNA methylation to generate 5-methylcarboxymethyl uridine (mcm[superscript 5]U) at the wobble position of certain tRNAs, a critical anticodon loop modification linked to DNA damage survival. We find that ABH8 interacts specifically with tRNAs containing mcm5U and that purified ABH8 complexes methylate RNA in vitro. Significantly, ABH8 depletion in human cells reduces endogenous levels of mcm[superscript 5]U in RNA and increases cellular sensitivity to DNA-damaging agents. Moreover, DNA-damaging agents induce ABH8 expression in an ATM-dependent manner. These results expand the role of mammalian AlkB proteins beyond that of direct DNA repair and support a regulatory mechanism in the DNA damage response pathway involving modulation of tRNA modification.
MIT Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1128/mcb.01604-09
