What is in a name? Rethinking SMUG1 in genome maintenance

Small base lesions in DNA are primarily repaired through the base excision repair pathway, which is initiated by DNA glycosylases. This review focuses on single-strand selective monofunctional uracil-DNA glycosylase (SMUG1), an enzyme whose name incompletely captures its broader biological roles. SMUG1 excises a wide range of substrates beyond uracil, shows a preference for double-stranded DNA, and has been reported to be a bifunctional DNA glycosylase with a weak lyase activity. Moreover, SMUG1 plays roles extending beyond DNA repair, including functions in RNA quality control and RNA biogenesis. Recently, genetic interactions have been described between SMUG1 and proteins that safeguard stressed replication forks, implicating a function for SMUG1 in cancer cell biology. Understanding SMUG1's full repertoire is key to uncovering its role in genome maintenance and unlocking its potential as a therapeutic target. Here, we review the biochemical properties reported for SMUG1 and its distinct functions from other uracil-DNA glycosylases in vivo. We also highlight the emerging role of SMUG1 in cancer cells and its potential as a therapeutic target, emphasizing the need to define the genetic and molecular contexts in which its modulation may be beneficial.