MBD4

Official Full Name

methyl-CpG binding domain 4, DNA glycosylase

Organism

Homo sapiens

GeneID

8930

Background

The protein encoded by this gene is a member of a family of nuclear proteins related by the presence of a methyl-CpG binding domain (MBD). These proteins are capable of binding specifically to methylated DNA, and some members can also repress transcription from methylated gene promoters. This protein contains an MBD domain at the N-terminus that functions both in binding to methylated DNA and in protein interactions and a C-terminal mismatch-specific glycosylase domain that is involved in DNA repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2013]

Synonyms

MED1; UVM1; TPDS2;

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Detailed Information

The methyl-CpG-binding domain 4 (MBD4), also known as methyl-CpG-binding endonuclease 1 (MED1), belongs to the MBD nuclear protein family. MBD4 consists of the N-terminal methylated CpG binding domain and the C-terminal DNA glycosidase domain. The study found that MBD4 plays an important role in DNA damage repair, transcriptional regulation and apoptosis regulation.

Main Features of MBD4

MBD4 is a multifunctional protein that plays an important role in DNA mismatch repair (MMR), genome surveillance, and apoptosis and tumorigenesis. The study confirmed that MBD4 interacts with the DNA mismatch repair protein and the MutL homolog MLH1 by yeast two-hybridization, and MBD4 can bind to methylated DNA. They also found that MBD4 has the characteristics of the MutH homolog in the MutHLS system and confirmed that MBD4 has a base excision repair (BER) enzymatic activity that specifically cleaves mismatched bases.

Figure 1. MBD4: guardian of the epigenetic galaxy. (Lambert Busque, et al. 2018)

It has been found that a single-stranded oligodeoxynucleotide (ssODN) containing methylated CpG can bind to MBD4 and induce efficient gene repair. The gene level correction efficiency induced by this binding is more than 10 times higher than that of the non-methylated CpG modified ssODN. Down-regulation of MBD4 expression by RNA interference can significantly reduce the gene repair efficiency of ssODN. This result shows that MBD4 can recruit a special repair mechanism. It is proved that methylated CpG-modified ssODN activates base excision by binding to MBD4. After the base excision repair (BER), the gene repair efficiency can be greatly improved.

The study found that MBD4 interacts with FADD, suggesting that MBD4 may have the ability to regulate apoptosis. MBD4 regulates apoptosis induced by factors such as DNA damage, Fas ligand, and cell separation. In view of the major role of FADD in apoptosis-induced apoptosis, wild-type (WT) and MBD4 knockout mice were injected with anti-Fas antibody Jo-2, which rapidly induced apoptosis in intestinal and hepatic epithelial cells. Compared with WT mice, MBD4 knockout mice were more sensitive to this treatment, and the apoptotic rate in liver and large and small intestines increased significantly. Expression of MBD4 in mouse embryonic fibroblasts (MEFs) derived from knockout of MBD4 mice also sensitized these cells to Fas ligand-induced apoptosis. Therefore, the effect of MBD4 on apoptosis depends on the cell type and its expression level.

MBD4 and Tumor

The SNP of the DNA damage repair gene can alter the structure and activity of the repair enzyme and affect tumor susceptibility. Mismatch repair is an important primary method of DNA damage repair. The study found that Glu346Lys high frequency polymorphism exists on the chromosome of MBD4 gene. This polymorphism affects the occurrence of malignant tumors such as gastrointestinal cancer, esophageal squamous cell carcinoma, and lung cancer. The study found that the Glu346Lys polymorphism in MBD4 is closely related to the susceptibility of colorectal cancer. This SNP locus is associated with a variety of tumor susceptibility and may be associated with its DNA repair function affecting MBD4.

Deletion of MBD4 expression indicates an increased susceptibility to cancer, and MBD4 mutations are often found in colon cancer with microsatellite instability. The results showed that among the 14 gastric cancer specimens with multiple microsatellite instability sites (MSI-H), the A10 repeat of the MBD4 gene of 4 specimens was deleted by 1 base pair. The study found that MBD4 is a microsatellite instability (MSI) target gene with mutations in medulloblastoma. MBD4 is closely related to microsatellite instability and tumorigenesis, and its mutation may reduce the ability of BER and even MMR, leading to tumorigenesis.

References:

Lambert Busque and Lucy A. Godley. (2018) MBD4: guardian of the epigenetic galaxy. 2018. 132: 1468-1469.
Ariyoshi, M. , Otani, J. , & Shirakawa, M. . (2015). Structure basis of versatile base recognition of mbd4. YAKUGAKU ZASSHI, 135(1), 3-9.
Hashimoto, H. . (2014). Structural and mutation studies of two dna demethylation related glycosylases: mbd4 and tdg. Biophysics, 10, 63-68.

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