Mettl2, or methyltransferase-like 2, is a key RNA methyltransferase involved in the methylation of cytosine 32 in the anticodon loop of specific tRNA isoacceptors to form 3-methylcytosine (m3C), which is crucial for maintaining the folding and base-pairing functions of the anticodon, and thus for cellular translation fidelity [1,2].

In mammals, Mettl2 forms a complex with DALRD3 protein to recognize particular arginine tRNAs for m3C modification. DALRD3-deficient human cells show nearly complete loss of the m3C modification in tRNA-Arg species. Mutations in DALRD3 that impair its interaction with Mettl2 and substrate tRNAs lead to reduced m3C modification in arginine tRNAs and are associated with developmental delay and early-onset epileptic encephalopathy, suggesting a crucial role for Mettl2-DALRD3-dependent tRNA modification in proper neurological development [1,3]. Additionally, in METTL2 null-mutant cells, there is an ∼30-40% reduction of m3C in total tRNA, and primer extension analysis located METTL2-modified m3C at position 32 of tRNAThr isoacceptors and tRNAArg(CCU) [2].

In conclusion, Mettl2 is essential for the m3C modification of specific tRNA species. Its function, in complex with DALRD3, is crucial for proper neurological development, as demonstrated by loss-of-function scenarios in human cells and individuals with DALRD3 mutations. The study of Mettl2 provides insights into the role of tRNA modification in normal physiological and disease-associated neurological processes.

References:

1. Lentini, Jenna M, Alsaif, Hessa S, Faqeih, Eissa, Alkuraya, Fowzan S, Fu, Dragony. 2020. DALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine tRNAs for 3-methylcytosine modification. In Nature communications, 11, 2510. doi:10.1038/s41467-020-16321-6. https://pubmed.ncbi.nlm.nih.gov/32427860/

2. Xu, Luang, Liu, Xinyu, Sheng, Na, Dedon, Peter C, Fu, Xin-Yuan. 2017. Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and mRNA in mice and humans. In The Journal of biological chemistry, 292, 14695-14703. doi:10.1074/jbc.M117.798298. https://pubmed.ncbi.nlm.nih.gov/28655767/

3. Zhang, Kejia, Löhner, Katharina, Lemmink, Henny H, de Silva, Naduni, Fu, Dragony. 2024. Epileptic encephalopathy linked to a DALRD3 missense variant that impairs tRNA modification. In HGG advances, 6, 100377. doi:10.1016/j.xhgg.2024.100377. https://pubmed.ncbi.nlm.nih.gov/39482881/