Methyl-CpG-binding domain protein 4 (MBD4)

Methyl-CpG-binding domain protein 4 (MBD4) is a nuclear DNA glycosylase enzyme that binds methylated CpG DNA and initiates base excision repair by removing mismatched thymine or uracil from G:T or G:U mismatches, especially those arising from spontaneous deamination of 5-methylcytosine in CpG dinucleotides[1][2][5]. It contains a methyl-CpG binding domain and a C-terminal glycosylase domain, allowing sequence-specific DNA interaction. MBD4 maintains genomic stability by preventing C→T transitions at CpG sites and interacts with DNA repair proteins such as MLH1. Germline or somatic mutations, as well as epigenetic silencing, of MBD4 are frequent in cancers with microsatellite instability and are associated with hypermutated tumor phenotypes. In rare cases, MBD4-deficient tumors may respond favorably to immune checkpoint inhibitors, making MBD4 status a potential biomarker for therapy selection[1]. Currently, there are no approved drugs directly targeting MBD4, but structural insights could inform future inhibitor development[2][5].

Other names

Methyl-CpG binding domain 4, DNA glycosylaseMBD4MED1Methyl-CpG-binding endonuclease 1Methyl-CpG-binding protein MBD4Mismatch-specific DNA N-glycosylaseTPDS2UVM13,N(4)-ethenocytosine glycosylaseG/5-fluorouracil mismatch glycosylaseG/T mismatch glycosylaseG/U mismatch glycosylaseputative methyl-CpG binding protein

N/A (no approved targeting drugs). The enzyme’s mechanism is through excising mismatched or damaged bases via base excision repair, potentially exploited in future therapies[5].