SMUG1 (single-strand-selective monofunctional uracil-DNA glycosylase 1) is a DNA glycosylase that initiates base excision repair by recognizing and excising uracil and oxidized pyrimidine lesions from DNA 1. The enzyme preferentially removes uracil (U), 5-formyluracil (fU), 5-hydroxyuracil (hoU), and 5-hydroxymethyluracil (hmU), with greater activity toward U/G mismatches than U/A base pairs 2. SMUG1 exhibits a unique helical wedge structure that facilitates damage recognition, distinguishing it mechanistically from the related uracil glycosylase UNG 1. Beyond canonical DNA repair, SMUG1 possesses moonlighting functions in RNA quality control, interacting with dyskerin (DKC1) to process modified RNA substrates and regulate rRNA maturation 34. Clinically, SMUG1 is emerging as a therapeutic target in cancer biology. SMUG1-mediated excision of genomic 5-hydroxymethyldeoxyuridine (hmdU) promotes synthetic lethality in BRCA-deficient cells treated with PARP inhibitors 5. Additionally, SMUG1 retention on chr12 in UNG-deficient cells triggers persistent abasic sites, PARP hyperactivation, and replication fork collapse, selectively killing homologous recombination-deficient tumors including those resistant to PARP inhibitors 6. These discoveries position SMUG1 inhibition or modulation as a promising strategy for treating BRCA-mutant and HR-deficient cancers.