TRMT2A (tRNA methyltransferase 2A) is an S-adenosyl-L-methionine-dependent methyltransferase that catalyzes the formation of 5-methyluridine (m5U) in cytosolic tRNAs and some mRNAs 1. The enzyme specifically methylates uridine at position 54 (m5U54) in tRNAs, with specificity achieved through a combination of modest binding preference and recognition of target uridine residues 2. TRMT2A contains an RNA recognition motif (RRM) in its N-terminus and a conserved uracil-C5-methyltransferase domain in its C-terminus 3. Beyond tRNA modification, TRMT2A contributes to translation fidelity, as knockdown reduces translation accuracy 2. The enzyme plays regulatory roles in cell cycle control, with overexpression decreasing cell proliferation and altering DNA content 3. Clinically, TRMT2A is implicated in polyglutamine (polyQ) diseases including Huntington's disease; silencing TRMT2A reduces polyQ-associated cell death and protein aggregation 4. Additionally, TRMT2A modulation by 5-fluorouracil contributes to cancer cytotoxicity 1, and dysregulated TRMT2A expression associates with severe COVID-19 disease 5. TRMT2A co-expression with COMT in the 22q11.2 region may contribute to neuropsychiatric disorders including schizophrenia 6.