TRMT1 (tRNA methyltransferase 1) is a critical enzyme that dimethylates guanine residue 26 of most nuclear- and mitochondrial-encoded tRNAs using S-adenosyl-L-methionine as a methyl donor 1. This N2,N2-dimethylguanosine (m2,2G) modification is essential for tRNA stability and function, particularly for tyrosine and serine tRNAs 2. TRMT1-catalyzed tRNA modifications promote both cellular protein synthesis and redox homeostasis, supporting proper cellular proliferation and oxidative stress survival 3. The enzyme functions through its conserved zinc finger domain, which is critical for tRNA binding and modification activity 3. TRMT1 exhibits dynamic subcellular localization, relocating from mitochondria and cytoplasm to nuclear punctate compartments upon neuronal activation, suggesting roles in neuronal plasticity 4. Bi-allelic TRMT1 variants cause autosomal recessive intellectual developmental disorder 68, characterized by developmental delay, intellectual disability, behavioral abnormalities, epilepsy, and facial dysmorphism 5. Disease-associated variants impair tRNA modification capacity and reduce tyrosine and serine tRNA levels 5. Additionally, SARS-CoV-2 main protease cleaves TRMT1 at a conserved mammalian site, eliminating tRNA modification activity and potentially contributing to COVID-19 pathogenesis 3.