Journal
NUCLEIC ACIDS RESEARCH
Volume 46, Issue 19, Pages 10302-10318Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky839
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Funding
- European Union's Horizon 2020 research and innovation programme, project T2DSystems [667191]
- Fonds National de la Recherche Scientifique (F.R.S.-FNRS)
- Actions de Recherche Concertees de la Communaute Francaise (ARC)
- FRFS-Welbio, the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody - European Union's Horizon 2020 research and innovation programme, EFPIA [115881]
- FRFS-Welbio, the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody - Swiss State Secretariat for Education, Research and Innovation (SERI) [115881, 16.0097]
- Societe Francophone du Diabete (SFD/Novartis)
- European Foundation for the study of Diabetes (EFSD)
- Brussels Capital Region-Innoviris
- Fondation ULB
- Wellcome Trust [102820/Z/13/Z]
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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 tRNA(Gln) and tRNA(iMeth) as two of its targets. Using RNA interference and induced pluripotent stem cell-derived pancreatic beta-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 beta-cells. We show that tRNA guanosine 9 hypomethylation leads to tRNA(Gln) fragmentation and that 5'-tRNA(Gln) fragments mediate TRMT10A deficiency-induced beta-cell death. This study unmasks tRNA hypomethylation and fragmentation as a hitherto unknown mechanism of pancre-atic beta-cell demise relevant to monogenic and polygenic forms of diabetes.
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