SMUG1 plays a crucial role in maintaining genomic integrity by excising uracil from both single-stranded (ssDNA) and double-stranded DNA (dsDNA). Uracil can be introduced into DNA through the spontaneous deamination of cytosine or the misincorporation of dUMP instead of dTMP during DNA replication . The removal of uracil is essential to prevent mutagenesis and maintain the stability of the genetic material.
SMUG1 operates by recognizing and binding to uracil-containing DNA, cleaving the N-glycosidic bond, and releasing free uracil. This action creates an abasic site, which is subsequently processed by other enzymes in the BER pathway to restore the correct DNA sequence .
SMUG1 is one of the major enzymes responsible for the repair of U:G mismatches in DNA. It acts as a backup for another uracil-DNA glycosylase, UNG, particularly in the context of antibody gene diversification. This redundancy ensures that uracil is efficiently removed from DNA, protecting against mutations and contributing to the immune response .
In addition to uracil, SMUG1 also removes several pyrimidine oxidation products, including the thymine oxidation product 5-hydroxymethyl uracil. This broad substrate specificity highlights the enzyme’s role in protecting DNA from various types of damage .
Research has shown that low SMUG1 expression is associated with aggressive cancer phenotypes and poor prognosis. For instance, in breast cancer, low SMUG1 mRNA and protein expression correlate with high histological grade, high mitotic index, and absence of hormonal receptors. These tumors often exhibit basal-like and triple-negative phenotypes, which are linked to more aggressive disease and poorer outcomes .
Interestingly, the expression levels of SMUG1 can also predict the response to adjuvant therapy. In estrogen receptor-positive (ER+) breast cancer patients receiving endocrine therapy, low SMUG1 expression is associated with poor survival. Conversely, in ER-negative (ER−) patients receiving chemotherapy, low SMUG1 expression is linked to improved survival .