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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.

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


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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