Mutations in the MUTYH gene, which encodes a DNA glycosylase, are associated with an increased risk of colorectal cancer (CRC), particularly in individuals with hereditary MUTYH-associated polyposis (MAP). MUTYH is an essential component of the base excision repair (BER) pathway, where it removes adenine resi-dues that are mispaired with 8-oxoguanine (8-oxoG), a major product of oxidative DNA damage. Loss of MUTYH function caused by pathogenic variants promotes the accumulation of oxidative DNA damage-associated mutations, including G:C→T:A transversions, thereby contributing to genomic instability and colo-rectal tumorigenesis. This review examines the pathogenic mechanisms underlying MAP and its characteristic phenotypic features. Structural and functional studies indicate that many pathogenic MUTYH variants result in reduced adenine DNA glycosylase activity, leading to impaired base excision repair. Potential therapeutic strate-gies aimed at restoring or compensating for defective MUTYH function are being investigated, including ap-proaches based on synthetic lethality. Increasing attention is also being paid to molecular genetic testing for bial-lelic pathogenic variants in the MUTYH gene, particularly in individuals with clinical or family histories sug-gestive of hereditary colorectal cancer or polyposis. Identification of such variants may enable more precise risk assessment and facilitate personalized surveillance and preventive management. Overall, advances in under-standing the role of MUTYH in genome maintenance have provided important insights into the pathogenesis of MAP and created opportunities for improving the diagnosis, risk stratification, and management of colorectal cancer.

Genome stability is fundamental to cell viability, the evolutionary stability of organisms, and the preservation of their functional integrity. Endogenous damage, particularly the oxidative modification of nitrogenous bases resulting from cellular metabolism, is one of the main factors disrupting DNA structure. To prevent the accumulation of mutations, cells utilize a base excision repair (BER) system in which DNA glycosylases play a pivotal role. These enzymes recognize and remove damaged or mismatched bases, thereby initiating a cascade of repair reactions. Adenine DNA glycosylases belonging to the MutY/MUTYH family are unique in that they do not directly remove damaged bases, but rather correct replication errors arising from oxidative damage to guanine. In bacteria, this function is performed by the MutY enzyme, whereas in eukaryotes it is performed by its homologue, MUTYH. These enzymes prevent G:C → T:A transition mutations from becoming fixed, thereby significantly reducing the level of spontaneous mutagenesis. This review discusses the role of DNA glycosylases in maintaining genomic stability, focusing on the molecular mechanisms of adenine DNA glycosylase function, their place in the BER system, evolutionary conservation, and their significance in biotechnology, molecular genetics, and applied research.

The Escherichia coli adenine-DNA glycosylase (MutY) and its human homologue, MUTYH, protect cells against oxygen-free radical-induced mutagenesis by excising regular adenine impaired with 8-oxo-7,8-dihydro-guanine (8oxoG) in the base excision repair (BER) pathway. However, removal of adenine by MutY and MUTYH from an A·8oxoG pair generated via misincorporation of an oxidized nucleotide during DNA synthesis might induce A·T→C·G transversions. Here, to examine MutY and MUTYH in vitro activities, we used short synthetic DNA duplexes in which the target adenine residue was positioned opposite a variety of DNA base modifications. MUTYH does not excise mismatched adenine in non-canonical DNA substrates, whereas MutY excises adenine mispaired with 1,3-d(GpNpG) cisplatin intra-strand crosslink. In addition, we characterized four MUTYH variants associated with cancer risk, which exhibit the following order of DNA glycosylase deficiency: WT ≥ G169D > G202E ≈ Y165C >> D222N. Human adenine-DNA glycosylase MUTYH and its mutant variants, contrary to bacterial MutY, are not prone to aberrant removal of regular adenine residues opposite modified residues in DNA duplexes. We hypothesize that E. coli MutY is prone to aberrant repair under certain conditions and that this may prevent incorporation of adenine opposite blocking lesions in the template strand.