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RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis | Nature Structural & Molecular Biology
Description:
Although cytosine-C5 methylation is a prominent modification of tRNAs, its functional significance has been unclear. Mice that lack both the Dnmt2 and NSun2 tRNA methyltransferases showed developmental and cellular differentiation defects, and loss of Dnmt2 and NSun2 was further associated with tRNA degradation and reduced rates of protein synthesis, suggesting that this modification promotes mouse development by supporting protein synthesis. 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.
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nature portfolio permissions reprints privacy policy stem cell research ovarian research nature advertising social media author information authors italy mediates myc-induced proliferation opioid-induced reward-seeking multisite-specific trna cytosine-c5 trna methylation manage preferences author correspondence trna-derived small rnas long-term opioid withdrawal springerlink instant access trna biology charges m5c methyltransferase rlmi personal data mrna-expression profiling data protection permissions gene expression cytosine-c5 methylation retina development rna cytosine methylation double mutants showed matthias schaefer trna methylation analysis codon-biased translation frank lyko dna methylation landscapes rna nucleotide methylation m5c-methyltransferase steady-state levels privacy embryonic stem cells stefanie kellner stress-induced cleavage reveals evolutionary links rna modification enzymes development competing financial interests dna methyltransferase homologue rnaโmethyltransferase misu rna methyltransferase misu molecular mechanisms
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- Do all modifications benefit all tRNAs?
- Grand challenge commentary: RNA epigenetics?
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description:Although cytosine-C5 methylation is a prominent modification of tRNAs, its functional significance has been unclear. Mice that lack both the Dnmt2 and NSun2 tRNA methyltransferases showed developmental and cellular differentiation defects, and loss of Dnmt2 and NSun2 was further associated with tRNA degradation and reduced rates of protein synthesis, suggesting that this modification promotes mouse development by supporting protein synthesis. 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.
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