TGS1 (trimethylguanosine synthase 1) is an RNA methyltransferase that catalyzes the conversion of 7-monomethylguanosine (m7G) caps to 2,2,7-trimethylguanosine (m2,2,7G) caps on snRNAs, snoRNAs, and human telomerase RNA (hTR) 1. This sequential N7 and N2 methylation is essential for proper nuclear localization and Cajal body formation [UniProt]. Beyond RNA capping, TGS1 plays critical roles in cancer biology and DNA repair. TGS1 is frequently overexpressed across multiple tumor types and correlates with poor prognosis 2. Mechanistically, TGS1-mediated hTR hypermethylation restrains telomere elongation by limiting telomerase assembly 1, though paradoxically, TGS1 depletion activates alternative lengthening of telomeres through RAD51-dependent recombination 3. Additionally, TGS1 participates in homologous recombination DNA repair through an ATM-TGS1-BRCA1 axis, where ATM phosphorylates TGS1 at S389/S531 to enhance BRCA1 recruitment to damage sites, conferring genotoxic therapy resistance in pancreatic cancer 4. Beyond cancer, TGS1 regulates hepatic gluconeogenesis through PKA-mediated phosphorylation and interaction with transcriptional coactivators 5. Clinically, TGS1 represents a promising therapeutic target for overcoming chemotherapy resistance and a potential biomarker for cancer prognosis and treatment response.