THUMPD2 is a catalytic methyltransferase that catalyzes S-adenosyl-L-methionine-dependent N(2)-methylation of guanosine at position 72 (m2G72) in U6 snRNA, a core component of the major spliceosome's catalytic center 12. This modification promotes efficient pre-mRNA splicing activity by fine-tuning splice site recognition, particularly affecting introns with suboptimal splice sites 12. THUMPD2 functions as part of the THUMPD2-TRM112 methyltransferase complex, where TRM112 acts as a stabilizing cofactor that enhances catalytic activity 13. Loss of THUMPD2 eliminates U6 m2G72 deposition, impairing global splicing efficiency and triggering nonsense-mediated mRNA decay of thousands of aberrantly spliced transcripts 2. Clinically, THUMPD2 dysregulation is implicated in retinal degeneration and age-related macular degeneration 2. Additionally, THUMPD2 downregulation appears associated with chemotherapy resistance in esophageal squamous cell carcinoma, suggesting a role in drug sensitivity 4. The conservation of this modification mechanism among vertebrates underscores its fundamental importance for managing the complexity of human splicing events.