Pancreatic β-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes
(2018) Nucleic Acids Research — Vol. 46, n° 19, p. 10302-10318 (2018)
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Igoillo-Esteve, Mariana 
- 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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Cosentino, C., Toivonen, S., Diaz Villamil, E., Atta, M., Ravanat, J.-L., Demine, S., Schiavo, 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 (Original work published 2018)