MBD4

MBD4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2MOE, 3IHO, 4DK9, 4E9E, 4E9F, 4E9G, 4E9H, 4EA4, 4EA5, 4LG7, 4OFA, 4OFE, 4OFH, 5CHZ
Identifiers
Aliases	MBD4, MED1, methyl-CpG binding domain 4, DNA glycosylase
External IDs	OMIM: 603574; MGI: 1333850; HomoloGene: 2916; GeneCards: MBD4; OMA:MBD4 - orthologs
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q21.3 Start 129,430,947 bp[1] End 129,440,179 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 E3|6 53.72 cM Start 115,817,658 bp[2] End 115,830,332 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte pylorus visceral pleura trabecular bone caput epididymis epithelium of nasopharynx optic nerve cardia renal medulla corpus epididymis Top expressed in lumbar spinal ganglion epithelium of male urethra genital tubercle tail of embryo vagina Rostral migratory stream ejaculatory duct pelvic part of vagina epiblast embryo More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding satellite DNA binding endodeoxyribonuclease activity protein binding catalytic activity hydrolase activity pyrimidine-specific mismatch base pair DNA N-glycosylase activity DNA N-glycosylase activity Cellular component chromatin nucleus nucleoplasm nuclear speck Biological process response to estradiol depyrimidination DNA repair cellular response to DNA damage stimulus response to radiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8930 17193 Ensembl ENSG00000129071 ENSMUSG00000030322 UniProt O95243 Q9Z2D7 RefSeq (mRNA) NM_001276270 NM_001276271 NM_001276272 NM_001276273 NM_003925 NM_010774 RefSeq (protein) NP_001263199 NP_001263200 NP_001263201 NP_001263202 NP_003916 NP_034904 Location (UCSC) Chr 3: 129.43 – 129.44 Mb Chr 6: 115.82 – 115.83 Mb PubMed search [3] [4]
Wikidata
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Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene.^[5][6][7]

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.^[8] These domains are separated by an intervening region that interacts with UHRF1, an E3 ubiquitin ligase, and USP7, a de-ubiquinating enzyme.^[9]

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.^[7]

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,^[8] and is potentially highly mutagenic. Deamination of cytosine (C) to uracil (U) and 5-methylcytosine (5mC) to thymine (T) generates G:U and G:T mismatches, respectively. Upon DNA replication, these mismatches cause C to T transition mutations. Notably, for 5mC deamination, these mutations arise predominantly in the context of CpG sites. The deamination rate of 5mC is approximately three times that of C. MBD4 protein binds preferentially to fully methylated CpG sites and to their deamination derivatives G:U and G:T base pairs.^[8] MBD4, which is employed in an initial step of base excision repair, specifically catalyzes the removal of T and U paired with guanine (G) within CpG sites.^[10]

G:U and G:T mismatches, upon DNA replication, give rise to C to T transition mutations.^[10] The mismatched U or T is usually removed by MBD4 before replication, thus avoiding mutation. Alternatively, for G:T mismatches, the T may be removed by thymine-DNA glycosylase. Mutations in the MBD4 gene (especially expansions/deletions in the polyadenine regions of the MBD4 gene) increase the genomic instability phenotype of a subset of MMR-defective tumors in mice, specifically contributing to elevated G:C to A:T transitions.^[11]

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.^[10][12] 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.^[10]

Mono- and biallelic germline mutations of MBD4 have been identified in acute myeloid leukemias, uveal melanomas, and glioblastomas.^[13][14][15] and monoallelic MBD4 germline mutations have been shown to predispose to uveal melanomas.^[16] 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.^[17]

Mutation of MBD4 occurs in about 4% of colorectal cancers.^[11] MBD4 mutations also occur in tumor samples of melanoma, ovarian, lung, esophageal and prostate cancers at frequencies between 0.5% and 8%.^[11]

MBD4 has a special relationship with DNA mismatch repair (MMR). MBD4 protein binds strongly to the MMR protein MLH1.^[6] A mutational deficiency in MBD4 causes down-regulation, at the protein level, of MMR proteins Mlh1, Msh2, Pms2, and Msh6 by 5.8-, 5.6-, 2.6-, and 2.7-fold, respectively.^[18] In colorectal cancers with mutations in MMR genes, co-occurrence of MBD4 mutations were found in 27% of cancers.^[11]

MBD4 mRNA expression is reduced in colorectal neoplasms due to methylation of the promoter region of MBD4.^[19] 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,^{[citation needed]} epigenetic deficiency of MBD4 is usually not evaluated, but might be of importance in such cancers as well.

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.^[15]

MBD4 has been shown to interact with MLH1^[6] and FADD.^[20]