The RNA methyltransferase METTL8 installs m3C32 in mitochondrial tRNAsThr/Ser(UCN) to optimise tRNA structure and mitochondrial translation

Nicole Kleiber, Nicolas Lemus-Diaz, Carina Stiller, Marleen Heinrichs, Mandy Mong-Quyen Mai, Philipp Hackert, Ricarda Richter-Dennerlein, Claudia Höbartner, Katherine E. Bohnsack () and Markus T. Bohnsack ()
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Nicole Kleiber: University Medical Centre Göttingen
Nicolas Lemus-Diaz: University Medical Centre Göttingen
Carina Stiller: Institute of Organic Chemistry, Universität Würzburg, Am Hubland
Marleen Heinrichs: University Medical Centre Göttingen
Mandy Mong-Quyen Mai: University Medical Centre Göttingen
Philipp Hackert: University Medical Centre Göttingen
Ricarda Richter-Dennerlein: University Medical Centre Göttingen
Claudia Höbartner: Institute of Organic Chemistry, Universität Würzburg, Am Hubland
Katherine E. Bohnsack: University Medical Centre Göttingen
Markus T. Bohnsack: University Medical Centre Göttingen

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Modified nucleotides in tRNAs are important determinants of folding, structure and function. Here we identify METTL8 as a mitochondrial matrix protein and active RNA methyltransferase responsible for installing m3C32 in the human mitochondrial (mt-)tRNAThr and mt-tRNASer(UCN). METTL8 crosslinks to the anticodon stem loop (ASL) of many mt-tRNAs in cells, raising the question of how methylation target specificity is achieved. Dissection of mt-tRNA recognition elements revealed U34G35 and t6A37/(ms2)i6A37, present concomitantly only in the ASLs of the two substrate mt-tRNAs, as key determinants for METTL8-mediated methylation of C32. Several lines of evidence demonstrate the influence of U34, G35, and the m3C32 and t6A37/(ms2)i6A37 modifications in mt-tRNAThr/Ser(UCN) on the structure of these mt-tRNAs. Although mt-tRNAThr/Ser(UCN) lacking METTL8-mediated m3C32 are efficiently aminoacylated and associate with mitochondrial ribosomes, mitochondrial translation is mildly impaired by lack of METTL8. Together these results define the cellular targets of METTL8 and shed new light on the role of m3C32 within mt-tRNAs.

Date: 2022
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DOI: 10.1038/s41467-021-27905-1

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