title: RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis.
abstract: The function of cytosine-C5 methylation, a widespread modification of tRNAs, has remained obscure, particularly in mammals. We have now developed a mouse strain defective in cytosine-C5 tRNA methylation, by disrupting both the Dnmt2 and the NSun2 tRNA methyltransferases. Although the lack of either enzyme alone has no detectable effects on mouse viability, double mutants showed a synthetic lethal interaction, with an underdeveloped phenotype and impaired cellular differentiation. tRNA methylation analysis of the double-knockout mice demonstrated complementary target-site specificities for Dnmt2 and NSun2 and a complete loss of cytosine-C5 tRNA methylation. Steady-state levels of unmethylated tRNAs were substantially reduced, and loss of Dnmt2 and NSun2 was further associated with reduced rates of overall protein synthesis. These results establish a biologically important function for cytosine-C5 tRNA methylation in mammals and suggest that this modification promotes mouse development by supporting protein synthesis.
authors.affiliation: Division of Epigenetics, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tuorto
authors.forename: Reinhard
authors.initials: R
authors.lastname: Liebers
authors.forename: Tanja
authors.initials: T
authors.lastname: Musch
authors.forename: Matthias
authors.initials: M
authors.lastname: Schaefer
authors.forename: Sarah
authors.initials: S
authors.lastname: Hofmann
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kellner
authors.forename: Michaela
authors.initials: M
authors.lastname: Frye
authors.forename: Mark
authors.initials: M
authors.lastname: Helm
authors.forename: Georg
authors.initials: G
authors.lastname: Stoecklin
authors.forename: Frank
authors.initials: F
authors.lastname: Lyko
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003596:Cytosine / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D014176:Protein Biosynthesis; D020871:RNA Stability; D012343:RNA, Transfer / Q000737:chemistry / Q000378:metabolism*
chemical_list: D003596:Cytosine; D012343:RNA, Transfer; C491786:Dnmt2 protein, mouse; D008780:Methyltransferases; C513146:Misu protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases