Projects per year
Abstract
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.
Original language | English |
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Pages (from-to) | 10302-10318 |
Number of pages | 17 |
Journal | Nucleic Acids Research |
Volume | 46 |
Issue number | 19 |
Early online date | 21 Sept 2018 |
DOIs | |
Publication status | Published - 2 Nov 2018 |
ASJC Scopus subject areas
- Genetics
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Dive into the research topics of 'Pancreatic β-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes'. Together they form a unique fingerprint.Projects
- 1 Finished
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Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)
Pearson, E. (Investigator)
16/02/15 → 15/08/21
Project: Research