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

par Cosentino, Cristina ;Toivonen, Sanna ;Diaz Villamil, Esteban ;Atta, Mohamed MA;Ravanat, Jean-Luc;Demine, Stéphane ;Schiavo, Andréa Alex ;Pachera, Nathalie ;Deglasse, Jean-Philippe;Jonas, Jean-Christophe JJC;Balboa, Diego;Otonkoski, Timo;Pearson, Ewan ER;Marchetti, Piero;Eizirik, Decio L. ;Cnop, Miriam ;Igoillo Esteve, Mariana
Référence Nucleic acids research, 46, 19, page (10302-10318)
Publication Publié, 2018-11-02

Article révisé par les pairs

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Résumé :

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.