TRMT1L is a tRNA methyltransferase that catalyzes N2,N2-dimethylguanosine (m2,2G) modification specifically at position 27 of tyrosine tRNA (tRNA-Tyr) using S-adenosyl-L-methionine as a methyl donor 12. This dimethylation is essential for efficient translation of tyrosine codons and maintains tRNA stability 12. Beyond its primary methyltransferase function, TRMT1L is also necessary for maintaining 3-(3-amino-3-carboxypropyl)uridine (acp3U) modifications in select cytoplasmic tRNAs through a process that can be uncoupled from catalytic activity 12. TRMT1L depletion results in marked decreases in tRNA-Tyr-GUA levels, reduced global translation rates, and increased sensitivity to oxidative stress 2. The enzyme dynamically relocates from nucleoli to nuclear punctate compartments upon neuronal activation, suggesting roles in neuronal plasticity 3. TRMT1L mutations have been associated with various disease contexts. Patient cells with TRMT1 family gene variants show dysregulated tRNA levels 1, and TRMT1L variants appear linked to idiopathic sudden sensorineural hearing loss through inflammation and oxidative-stress pathways 4. Additionally, TRMT1L has been identified as part of cancer-associated gene signatures in breast cancer and prostate cancer prognosis 56.