MBD4

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Protein-coding gene in the species Homo sapiens

title: "MBD4" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public description: "Protein-coding gene in the species Homo sapiens" topic_path: "uncategorized" source: "https://en.wikipedia.org/wiki/MBD4" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Protein-coding gene in the species Homo sapiens ::

Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene.

Structure

Human MBD4 protein has 580 amino acids with a methyl-CpG-binding domain at amino acids 82–147 and a C-terminal DNA glycosylase domain at amino acids 426–580. These domains are separated by an intervening region that interacts with UHRF1, an E3 ubiquitin ligase, and USP7, a de-ubiquinating enzyme.

Function

DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 (this gene) comprise a family of nuclear proteins related by the presence in each of a methyl-CpG-binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MBD4 may function to mediate the biological consequences of the methylation signal. In addition, MBD4 has protein sequence similarity to bacterial DNA repair enzymes and thus may have some function in DNA repair. Further, MBD4 gene mutations are detected in tumors with primary microsatellite instability (MSI), a form of genomic instability associated with defective DNA mismatch repair, and MBD4 gene meets 4 of 5 criteria of a bona fide MIS target gene.

Deaminated bases as targets

::figure[src="https://upload.wikimedia.org/wikipedia/commons/a/a9/DesaminierungCtoU.png"] ::

Bases in DNA decay spontaneously, and this decay includes hydrolytic deamination of purines and pyrimidines that contain an exocyclic amino group (see image). Hypoxanthine and xanthine are generated at a relatively slow rate by deamination of adenine and guanine, respectively. However, deamination of pyrimidines occurs at a 50-fold higher rate of approximately 200–300 events per cell per day,

Mutational importance of targets

G:U and G:T mismatches, upon DNA replication, give rise to C to T transition mutations.

About 1/3 of all intragenic single base pair mutations in human cancers occur in CpG dinucleotides and are the result of C to T or G to A transitions. These transitions comprise the most frequent mutations in human cancer. For example, nearly 50% of somatic mutations of the tumor suppressor gene p53 in colorectal cancer are G:C to A:T transitions within CpG sites.

Clinical significance in cancer

Germline mutations of MBD4

Mono- and biallelic germline mutations of MBD4 have been identified in acute myeloid leukemias, uveal melanomas, and glioblastomas. and monoallelic MBD4 germline mutations have been shown to predispose to uveal melanomas. These cases presented an inactivation of the second allele of MBD4 in tumor and were associated with a subsequent very high mutation burden at CpG dinucleotides. An MBD4 monoallelic deletion was found amon Israeli Christian Arabs. This heterozygous mutation increased somatic mutation rate in blood cells among carriers.

Somatic mutations of MBD4

Mutation of MBD4 occurs in about 4% of colorectal cancers. MBD4 mutations also occur in tumor samples of melanoma, ovarian, lung, esophageal and prostate cancers at frequencies between 0.5% and 8%.

MBD4 has a special relationship with DNA mismatch repair (MMR). MBD4 protein binds strongly to the MMR protein MLH1. In colorectal cancers with mutations in MMR genes, co-occurrence of MBD4 mutations were found in 27% of cancers.

Epigenetic silencing

MBD4 mRNA expression is reduced in colorectal neoplasms due to methylation of the promoter region of MBD4. A majority of histologically normal fields surrounding the neoplastic growths also show reduced MBD4 mRNA expression (a field defect) compared to histologically normal tissue from individuals who never had a colonic neoplasm. This indicates that an epigenetic deficiency in MBD4 expression is a frequent early event in colorectal tumorigenesis.

While other DNA repair genes, such as MGMT and MLH1, are often evaluated for epigenetic repression in many types of cancer, epigenetic deficiency of MBD4 is usually not evaluated, but might be of importance in such cancers as well.

Response to checkpoint inhibitors

MBD4-associated hypermutated profile was shown to be associated with a tumor regression when a uveal melanoma patient was treated with a checkpoint inhibitor making these mutations potential biomarkers to treat cancers.

Interactions

MBD4 has been shown to interact with MLH1

References

References

  1. (Nov 1998). "Identification and Characterization of a Family of Mammalian Methyl-CpG Binding Proteins". Mol Cell Biol.
  2. (May 1999). "MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1". Proc Natl Acad Sci U S A.
  3. "Entrez Gene: MBD4 methyl-CpG binding domain protein 4".
  4. (Aug 2015). "Role of base excision repair in maintaining the genetic and epigenetic integrity of CpG sites". DNA Repair.
  5. (Mar 2015). "MBD4 interacts with and recruits USP7 to heterochromatic foci". Journal of Cellular Biochemistry.
  6. (2013). "MBD4 and TDG: multifaceted DNA glycosylases with ever expanding biological roles". Mutation Research.
  7. (Oct 2015). "Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis". Oncotarget.
  8. (Jul 2018). "MBD4 guards against methylation damage and germline deficiency predisposes to clonal hematopoiesis and early-onset AML". Blood.
  9. (2020). "Pan-cancer analysis of whole genomes". Nature.
  10. (May 2018). "Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors.". Nature Communications.
  11. (April 2020). "Germline MBD4 mutations and predisposition to uveal melanoma.". Journal of the National Cancer Institute.
  12. (2025-09-04). "A founder heterozygous mutation in Methyl-CpG binding domain protein 4 (MBD4) prevalent among Israeli Christian Arabs predisposes to increased mutagenesis". Haematologica.
  13. (Dec 2003). "The base excision repair enzyme MED1 mediates DNA damage response to antitumor drugs and is associated with mismatch repair system integrity". Proceedings of the National Academy of Sciences of the United States of America.
  14. (Jan 2009). "Epigenetic downregulation of the DNA repair gene MED1/MBD4 in colorectal and ovarian cancer". Cancer Biology & Therapy.

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