Pancreatic β-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes

Nucleic Acids Res. 2018 Nov 2;46(19):10302-10318. doi: 10.1093/nar/gky839.


Transfer RNAs (tRNAs) are non-coding RNA molecules essential for protein synthesis. Post-transcriptionally they are heavily modified to improve their function, folding and stability. Intronic polymorphisms in CDKAL1, a tRNA methylthiotransferase, are associated with increased type 2 diabetes risk. Loss-of-function mutations in TRMT10A, a tRNA methyltransferase, are a monogenic cause of early onset diabetes and microcephaly. Here we confirm the role of TRMT10A as a guanosine 9 tRNA methyltransferase, and identify tRNAGln and tRNAiMeth as two of its targets. Using RNA interference and induced pluripotent stem cell-derived pancreatic β-like cells from healthy controls and TRMT10A-deficient patients we demonstrate that TRMT10A deficiency induces oxidative stress and triggers the intrinsic pathway of apoptosis in β-cells. We show that tRNA guanosine 9 hypomethylation leads to tRNAGln fragmentation and that 5'-tRNAGln fragments mediate TRMT10A deficiency-induced β-cell death. This study unmasks tRNA hypomethylation and fragmentation as a hitherto unknown mechanism of pancreatic β-cell demise relevant to monogenic and polygenic forms of diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Apoptosis / genetics
  • Cell Death / genetics
  • Cell Differentiation / genetics
  • Cells, Cultured
  • DNA Fragmentation
  • DNA Methylation*
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / metabolism
  • Genetic Linkage
  • Humans
  • Induced Pluripotent Stem Cells / physiology
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / physiology
  • Methyltransferases / deficiency
  • Methyltransferases / genetics*
  • Methyltransferases / metabolism
  • Middle Aged
  • Mutation
  • RNA, Transfer / metabolism*
  • Rats


  • RNA, Transfer
  • Methyltransferases
  • TRMT10A protein, human