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

Cristina Cosentino, Sanna Toivonen, Esteban Diaz Villamil, Mohamed Atta, Jean-Luc Ravanat, Stéphane Demine, Andrea Alex Schiavo, Nathalie Pachera, Jean-Philippe Deglasse, Jean-Christophe Jonas, Diego Balboa, Timo Otonkoski, Ewan R. Pearson, Piero Marchetti, Décio L Eizirik, Miriam Cnop (Lead / Corresponding author), Mariana Igoillo-Esteve (Lead / Corresponding author)

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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 languageEnglish
Pages (from-to)10302-10318
Number of pages17
JournalNucleic Acids Research
Volume46
Issue number19
Early online date21 Sep 2018
DOIs
Publication statusPublished - 2 Nov 2018

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    Cosentino, C., Toivonen, S., Diaz Villamil, E., Atta, M., Ravanat, J-L., Demine, S., Schiavo, A. A., Pachera, N., Deglasse, J-P., Jonas, J-C., Balboa, D., Otonkoski, T., Pearson, E. R., Marchetti, P., Eizirik, D. L., Cnop, M., & Igoillo-Esteve, M. (2018). Pancreatic β-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes. Nucleic Acids Research, 46(19), 10302-10318. https://doi.org/10.1093/nar/gky839