MBD4 (methyl-CpG binding domain 4, DNA glycosylase) is a mismatch-specific DNA N-glycosylase that plays a crucial role in base excision repair by removing thymine, uracil, and 5-fluorouracil from G:T and G:U mismatches, particularly within CpG contexts 1. The protein contains an N-terminal methyl-CpG binding domain and a C-terminal catalytic domain with glycosylase activity, allowing it to repair G:T mismatches arising from spontaneous deamination of 5-methylcytosine to thymine 1. MBD4 functions as a caretaker of genomic fidelity at CpG sites and interacts with the mismatch repair protein MLH1 1. Germline bi-allelic loss-of-function variants in MBD4 cause an autosomal recessive multi-tumor predisposition syndrome characterized by adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma 2. The colorectal adenomas from MBD4-deficient individuals exhibit a mutator phenotype consistent with mutational signature SBS1 2. MBD4 represents one of the major G:T glycosylases alongside TDG and has been implicated in apoptosis regulation 3. Clinical significance includes its role in hereditary adenomatous polyposis syndromes and various cancers, warranting inclusion in genetic testing panels for polyposis and multi-tumor phenotypes 24.