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

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

Author information

1
ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium.
2
CEA/Grenoble, DRF/BIG/LCBM UMR5249, Grenoble, France.
3
Université Grenoble Alpes, CEA, CNRS INAC, SyMMES UMR 5819, Grenoble, France.
4
Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle d' Endocrinologie, Diabète et Nutrition, Brussels, Belgium.
5
Research Programs Unit, Molecular Neurology and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
6
Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
7
Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, UK.
8
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
9
Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.

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.

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