6533b856fe1ef96bd12b1c57
RESEARCH PRODUCT
Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders.
Helmut FuchsShobbir HussainPatrick LombardMichaela FryeMargus LukkJernej UleMartyna C. PopisClaudia KutterPeter HumphreysDuncan T. OdomMartin Hrabe De AngelisLore BeckerLillian GarrettRagnhildur Thóra KáradóttirValerie Gailus-durnerSabine DietmannLucas TrepsWolfgang WurstThomas KlopstockSandra BlancoJoana V. FloresMark HelmSabine M. HölterStefanie KellnerJoseph G. Gleesonsubject
Small RNARNA methylationBiologyNSun2MethylationGeneral Biochemistry Genetics and Molecular Biology03 medical and health sciencesMisuMice0302 clinical medicineRNA TransferGene expressionAnimalsHumans5‐methylcytidine ; Misu ; Nsun2 ; Rna ModificationMolecular Biology030304 developmental biology5-methylcytidineRegulation of gene expression0303 health sciencesTRNA methylationGeneral Immunology and MicrobiologyGeneral NeuroscienceGene Expression ProfilingRNABrainArticlesMethylationMethyltransferasesRibonuclease PancreaticRNA modificationMolecular biologyOxidative StressGene Expression RegulationTransfer RNANervous System Diseases030217 neurology & neurosurgery5‐methylcytidinedescription
Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post-transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine-5 RNA methylomes in patient fibroblasts and NSun2-deficient mice, we find that loss of cytosine-5 RNA methylation increases the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5' tRNA-derived small RNA fragments. Accumulation of 5' tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site-specific NSun2-mediated methylation and that the presence of 5' tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2-deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2-mediated tRNA methylation contributes to human diseases via stress-induced RNA cleavage.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-09-17 |