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Cracking the case of m7G modification in human tRNAs

Nature Structural & Molecular Biology volume 30, pages 242–243 (2023)Cite this article

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The RNA methyltransferase (MTase) METTL1 catalyzes N7-methylguanosine (m7G) modification at position 46 in human transfer RNAs (tRNAs). Its dysregulation drives tumorigenesis in many cancer types. Two papers now reveal the structural basis of this tRNA maturation event.

In recent years, deficiencies and dysregulation of tRNA modifications have been linked to human disease, including mitochondrial diseases, neurological disorders and cancer5,6, which highlights the importance of understanding the mechanisms underlying modification deposition. In two recent studies published in Nature, Li et al.7 and Ruiz-Arroyo et al.8 have made considerable progress in this direction by providing structural and biochemical insights into the mechanisms of tRNA methylation by the human m7G46 MTase complex METTL1–WDR4. In these studies, they obtained cryo-electron microscopy (cryo-EM) structures of complexes between the human METTL1–WDR4 complex and different tRNAs (tRNAPhe, tRNAVal and tRNALys3) in different states of SAM or SAH presence in the active site of METTL1: in the presence of SAH, for the structure with tRNAPhe at 3.3-Å resolution; with no ligand, for the structure with tRNAVal at 3.6-Å resolution; and with no cofactor (3.7-Å resolution), with SAM (4.0-Å resolution) or with SAH (3.5-Å resolution), for the three structures solved with tRNALys3. METTL1 and WDR4 form a stable complex with extensive intermolecular interactions crucial for optimal MTase activity.

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Fig. 1: m7G46 modification in tRNA by METTL1–WDR4.

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Acknowledgements

The authors acknowledge support from the CNRS, the Agence Nationale de la Recherche (ANR-19-CE07-0028 and ANR-19-CE44-0013) and the LabEx DYNAMO (ANR-11-LABX-0011).

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  1. Microbial Gene Expression Unit, Institute of Physico-Chemical Biology (IBPC), Centre National de la Recherche Scientifique, Université Paris Cité, Paris, France

    Pierre Barraud & Carine Tisné

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  1. Pierre Barraud
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Correspondence to Carine Tisné.

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Barraud, P., Tisné, C. Cracking the case of m7G modification in human tRNAs. Nat Struct Mol Biol 30, 242–243 (2023). https://doi.org/10.1038/s41594-023-00937-5

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