MBD4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMBD4, MED1, methyl-CpG binding domain 4, DNA glycosylase
External IDsOMIM: 603574 MGI: 1333850 HomoloGene: 2916 GeneCards: MBD4
Orthologs
SpeciesHumanMouse
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 MbChr 6: 115.82 – 115.83 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene.[5][6][7]

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

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.[7]

Deaminated bases as targets

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]

Mutational importance of targets

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]

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.[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.

Somatic mutations of MBD4

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.[17] In colorectal cancers with mutations in MMR genes, co-occurrence of MBD4 mutations were found in 27% of cancers.[11]

Epigenetic silencing

MBD4 mRNA expression is reduced in colorectal neoplasms due to methylation of the promoter region of MBD4.[18] 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.[15]

Interactions

MBD4 has been shown to interact with MLH1[6] and FADD.[19]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000129071 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030322 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Hendrich B, Bird A (Nov 1998). "Identification and Characterization of a Family of Mammalian Methyl-CpG Binding Proteins". Mol Cell Biol. 18 (11): 6538–47. doi:10.1128/mcb.18.11.6538. PMC 109239. PMID 9774669.
  6. 1 2 3 Bellacosa A, Cicchillitti L, Schepis F, Riccio A, Yeung AT, Matsumoto Y, Golemis EA, Genuardi M, Neri G (May 1999). "MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1". Proc Natl Acad Sci U S A. 96 (7): 3969–74. Bibcode:1999PNAS...96.3969B. doi:10.1073/pnas.96.7.3969. PMC 22404. PMID 10097147.
  7. 1 2 "Entrez Gene: MBD4 methyl-CpG binding domain protein 4".
  8. 1 2 3 Bellacosa A, Drohat AC (Aug 2015). "Role of base excision repair in maintaining the genetic and epigenetic integrity of CpG sites". DNA Repair. 32: 33–42. doi:10.1016/j.dnarep.2015.04.011. PMC 4903958. PMID 26021671.
  9. ↑ Meng H, Harrison DJ, Meehan RR (Mar 2015). "MBD4 interacts with and recruits USP7 to heterochromatic foci". Journal of Cellular Biochemistry. 116 (3): 476–85. doi:10.1002/jcb.25001. PMC 4964934. PMID 25358258.
  10. 1 2 3 4 Sjolund AB, Senejani AG, Sweasy JB (2013). "MBD4 and TDG: multifaceted DNA glycosylases with ever expanding biological roles". Mutation Research. 743–744: 12–25. doi:10.1016/j.mrfmmm.2012.11.001. PMC 3661743. PMID 23195996.
  11. 1 2 3 4 Tricarico R, Cortellino S, Riccio A, Jagmohan-Changur S, Van der Klift H, Wijnen J, Turner D, Ventura A, Rovella V, Percesepe A, Lucci-Cordisco E, Radice P, Bertario L, Pedroni M, Ponz de Leon M, Mancuso P, Devarajan K, Cai KQ, Klein-Szanto AJ, Neri G, Møller P, Viel A, Genuardi M, Fodde R, Bellacosa A (Oct 2015). "Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis" (PDF). Oncotarget. 6 (40): 42892–904. doi:10.18632/oncotarget.5740. PMC 4767479. PMID 26503472.
  12. ↑ Cooper DN, Youssoufian H (Feb 1988). "The CpG dinucleotide and human genetic disease". Human Genetics. 78 (2): 151–5. doi:10.1007/bf00278187. PMID 3338800. S2CID 41948691.
  13. ↑ Sanders MA, Chew E, et al. (Jul 2018). "MBD4 guards against methylation damage and germline deficiency predisposes to clonal hematopoiesis and early-onset AML". Blood. 132 (14): 1526–1534. bioRxiv 10.1101/180588. doi:10.1182/blood-2018-05-852566. PMC 6172562. PMID 30049810.
  14. ↑ Waszak SM, Tiao G, Zhu B, Rausch T, et al. (Nov 2017). "Germline determinants of the somatic mutation landscape in 2,642 cancer genomes". bioRxiv 10.1101/208330.
  15. 1 2 Rodrigues M, Mobuchon L, Houy A, Fiévet A, Gardrat S, Barnhill RL, Popova T, Servois V, Rampanou A, Mouton A, Dayot S, Raynal V, Galut M, Putterman M, Tick S, Cassoux N, Roman-Roman S, Bidard FC, Lantz O, Mariani P, Piperno-Neumann S, Stern MH (May 2018). "Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors". Nature Communications. 9 (1): 1866. Bibcode:2018NatCo...9.1866R. doi:10.1038/s41467-018-04322-5. PMC 5951831. PMID 29760383.
  16. ↑ Derrien AC, Rodrigues M, Eeckhoutte A, Dayot S, Houy A, Mobuchon L, Gardrat S, Lequin D, Ballet S, Pierron G, Alsafadi S, Mariani O, El-Marjou A, Matet A, Colas C, Cassoux N, Stern MH (April 2020). "Germline MBD4 mutations and predisposition to uveal melanoma". Journal of the National Cancer Institute. 112 (1): 80–87. doi:10.1093/jnci/djaa047. PMC 7781447. PMID 32239153.
  17. ↑ Cortellino S, Turner D, Masciullo V, Schepis F, Albino D, Daniel R, Skalka AM, Meropol NJ, Alberti C, Larue L, Bellacosa A (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. 100 (25): 15071–6. doi:10.1073/pnas.2334585100. PMC 299910. PMID 14614141.
  18. ↑ Howard JH, Frolov A, Tzeng CW, Stewart A, Midzak A, Majmundar A, Godwin A, Heslin M, Bellacosa A, Arnoletti JP (Jan 2009). "Epigenetic downregulation of the DNA repair gene MED1/MBD4 in colorectal and ovarian cancer". Cancer Biology & Therapy. 8 (1): 94–100. doi:10.4161/cbt.8.1.7469. PMC 2683899. PMID 19127118.
  19. ↑ Screaton RA, Kiessling S, Sansom OJ, Millar CB, Maddison K, Bird A, Clarke AR, Frisch SM (Apr 2003). "Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: A potential link between genome surveillance and apoptosis". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5211–6. Bibcode:2003PNAS..100.5211S. doi:10.1073/pnas.0431215100. PMC 154324. PMID 12702765.

Further reading

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