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Gene Review

DNMT3B  -  DNA (cytosine-5-)-methyltransferase 3 beta

Homo sapiens

Synonyms: DNA (cytosine-5)-methyltransferase 3B, DNA MTase HsaIIIB, DNA methyltransferase HsaIIIB, Dnmt3b, ICF, ...
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Disease relevance of DNMT3B


Psychiatry related information on DNMT3B

  • SICI was significantly enhanced in NREM 3/4 as compared to wakefulness and all other sleep stages whereas in NREM 2 neither SICI nor ICF differed from wakefulness [7].
  • Here, we specifically asked whether in the motor cortex short intracortical inhibition (SICI) and facilitation (ICF) can be elicited at all in sleep using the paired-pulse TMS protocol, and if so, how SICI and ICF vary across sleep stages [7].
  • Physical activity behaviour and its determinants were integrated into the ICF model [8].
  • SICI was decreased after 32 min of motor skill training but no changes were observed in ICF [9].
  • Most recipients in ICF's/MR were nonelderly adults with severe or profound mental retardation who were in an ICF/MR for the entire year [10].

High impact information on DNMT3B

  • Letter: ICF instead of DIC [11]?
  • ICF syndrome is the only genetic disorder known to involve constitutive abnormalities of genomic methylation patterns [12].
  • Classical satellite DNA is normally heavily methylated at cytosine residues, but in ICF syndrome it is almost completely unmethylated in all tissues [12].
  • The recessive autosomal disorder known as ICF syndrome (for immunodeficiency, centromere instability and facial anomalies; Mendelian Inheritance in Man number 242860) is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood [12].
  • Although enzymes have been identified that can methylate DNA de novo (Dnmt3a and Dnmt3b) (14), it is unknown how specific patterns of methylation are established in the genome [13].

Chemical compound and disease context of DNMT3B

  • To analyse the protein structure and consequences of ICF-causing mutations, we modelled the structure of the DNMT3B methyltransferase domain based on Haemophilus haemolyticus protein in complex with the cofactor AdoMet and the target DNA sequence [14].
  • In an 8-week open-trial substitution study, 64 subjects with seizure disorders living at an ICF/MR were randomly assigned to either brand-named Depakene or generic Valproic Acid USP (Solvay) medication [15].

Biological context of DNMT3B

  • This decrease in DNMT3B mRNA results in a significant reduction in de novo methylation activities [1].
  • Here we describe a mechanism by which HDAC inhibitors affect DNA methylation through their regulation on DNMT3B, a methyltransferase responsible for de novo DNA methylation [1].
  • Further experiments indicated that TSA decreases DNMT3B mRNA stability and reduces its half-life from approximately 4 to 2.5 hours [1].
  • Transient overexpression of DNMT1 or DNMT3B suppressed the luciferase expression from both methylated and unmethylated pHrD-IRES-Luc, a reporter plasmid where the rDNA promoter drives luciferase expression [16].
  • We have mapped human DNMT3A and DNMT3B to chromosomes 2p23 and 20q11.2 respectively, and determined the DNMT3B genomic structure [17].

Anatomical context of DNMT3B


Associations of DNMT3B with chemical compounds

  • Although the poor prognosis associated with DNMT3B overexpression was confirmed by univariate analysis in an independent series of 98 postmenopausal women exclusively treated with adjuvant tamoxifen therapy (P = 0.0036), DNMT3B expression status did not persist as an independent prognostic factor in multivariate analysis [2].
  • The DNMT3A and DNMT3B show high homology in the carboxy terminal catalytic domain and contain a conserved cysteine-rich region, which shares homology with the X-linked ATRX gene of the SNF2/SWI family [17].
  • Recently, we identified a C-->T transition at a novel promoter region of cytosine DNA-methyltransferase-3B (DNMT3B) and found that this polymorphic transition significantly increases the promoter activity [4].
  • No relationship was observed between global genomic 5-methylcytosine levels and relative amounts of RNA for DNA methyltransferases DNMT1, DNMT3A, and DNMT3B [20].
  • The silencing of GADD45G could be reversed by 5-aza-2'-deoxycytidine or genetic double knockout of DNMT1 and DNMT3B, indicating a direct epigenetic mechanism [21].

Physical interactions of DNMT3B


Co-localisations of DNMT3B


Other interactions of DNMT3B

  • Recently, two new mammalian DNA methyltransferase genes have been identified, which are referred to as DNMT3A and DNMT3B [23].
  • Unlike DNMT1, both the wild type and catalytically inactive DNMT3B mutant can suppress rDNA promoter irrespective of its methylation status [16].
  • Previous studies have shown that DNMT3L physically associates with the active de novo DNA methyltransferases, DNMT3A and DNMT3B, and stimulates their catalytic activities in a cell culture system [24].
  • Here we demonstrate that DNMT3B associates with four chromatin-associated enzymatic activities common to transcriptionally repressed, heterochromatic regions of the genome: DNA methyltransferase, histone deacetylase, ATPase, and histone methylase activities [22].
  • DNMT3B overexpression was significantly related to Scarff, Bloom, and Richardson histopathological grade III (P = 0.002), ERalpha negativity (P = 0.0015), and strong MKI67 expression (P = 3 x 10(-6)) [2].

Analytical, diagnostic and therapeutic context of DNMT3B

  • Immunofluorescence analysis and biochemical fractionation showed that all three DNMTs (DNMT1, DNMT3A, and DNMT3B) are associated with the inactive rDNA in the nucleolus [16].
  • In univariate analysis, DNMT3B overexpression was associated with poor relapse-free survival in the subgroup of patients who received adjuvant hormone therapy (with or without chemotherapy; P = 0.0064) [2].
  • Western blot analysis confirmed opposite expression patterns of DNMT1 and DNMT3B protein in endometrioid and serous cancers [25].
  • In this hospital-based case-control study of 319 patients with incident lung cancer and 340 healthy controls frequency matched on age (+/-5 years), sex, ethnicity, and smoking status, we genotyped subjects for this DNMT3B promoter polymorphism to determine the association between this genetic variant and risk of lung cancer [4].
  • Microarray expression analysis was done on B-cell lymphoblastoid cell lines (LCLs) from ICF patients with diverse DNMT3B mutations and on control LCLs using oligonucleotide arrays for approximately 5600 different genes, 510 of which showed a lymphoid lineage-restricted expression pattern among several different lineages tested [26].


  1. Histone deacetylase inhibitors decrease DNA methyltransferase-3B messenger RNA stability and down-regulate de novo DNA methyltransferase activity in human endometrial cells. Xiong, Y., Dowdy, S.C., Podratz, K.C., Jin, F., Attewell, J.R., Eberhardt, N.L., Jiang, S.W. Cancer Res. (2005) [Pubmed]
  2. Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas. Girault, I., Tozlu, S., Lidereau, R., Bièche, I. Clin. Cancer Res. (2003) [Pubmed]
  3. Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Mizuno , S., Chijiwa, T., Okamura, T., Akashi, K., Fukumaki, Y., Niho, Y., Sasaki, H. Blood (2001) [Pubmed]
  4. A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer. Shen, H., Wang, L., Spitz, M.R., Hong, W.K., Mao, L., Wei, Q. Cancer Res. (2002) [Pubmed]
  5. Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cui, H., Onyango, P., Brandenburg, S., Wu, Y., Hsieh, C.L., Feinberg, A.P. Cancer Res. (2002) [Pubmed]
  6. DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer. Nosho, K., Shima, K., Irahara, N., Kure, S., Baba, Y., Kirkner, G.J., Chen, L., Gokhale, S., Hazra, A., Spiegelman, D., Giovannucci, E.L., Jaenisch, R., Fuchs, C.S., Ogino, S. Clin. Cancer Res. (2009) [Pubmed]
  7. Inhibitory and excitatory intracortical circuits across the human sleep-wake cycle using paired-pulse transcranial magnetic stimulation. Salih, F., Khatami, R., Steinheimer, S., Hummel, O., Kühn, A., Grosse, P. J. Physiol. (Lond.) (2005) [Pubmed]
  8. Physical activity for people with a disability: a conceptual model. van der Ploeg, H.P., van der Beek, A.J., van der Woude, L.H., van Mechelen, W. Sports medicine (Auckland, N.Z.) (2004) [Pubmed]
  9. Motor skill training induces changes in the excitability of the leg cortical area in healthy humans. Perez, M.A., Lungholt, B.K., Nyborg, K., Nielsen, J.B. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. (2004) [Pubmed]
  10. Medicaid recipients in intermediate care facilities for the mentally retarded. Burwell, B., Clauser, S., Hall, M.J., Simon, J. Health care financing review. (1987) [Pubmed]
  11. Letter: ICF instead of DIC? Hardaway, R.M. N. Engl. J. Med. (1975) [Pubmed]
  12. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Xu, G.L., Bestor, T.H., Bourc'his, D., Hsieh, C.L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J.J., Viegas-Péquignot, E. Nature (1999) [Pubmed]
  13. Epigenetic reprogramming in mammalian development. Reik, W., Dean, W., Walter, J. Science (2001) [Pubmed]
  14. Structural basis of ICF-causing mutations in the methyltransferase domain of DNMT3B. Lappalainen, I., Vihinen, M. Protein Eng. (2002) [Pubmed]
  15. Effects of switching from Depakene to generic valproic acid on individuals with mental retardation. Vadney, V.J., Kraushaar, K.W. Mental retardation. (1997) [Pubmed]
  16. Role of DNA methyltransferases in regulation of human ribosomal RNA gene transcription. Majumder, S., Ghoshal, K., Datta, J., Smith, D.S., Bai, S., Jacob, S.T. J. Biol. Chem. (2006) [Pubmed]
  17. Cloning, expression and chromosome locations of the human DNMT3 gene family. Xie, S., Wang, Z., Okano, M., Nogami, M., Li, Y., He, W.W., Okumura, K., Li, E. Gene (1999) [Pubmed]
  18. Identification of 11 pseudogenes in the DNA methyltransferase gene family in rodents and humans and implications for the functional loci. Lees-Murdock, D.J., McLoughlin, G.A., McDaid, J.R., Quinn, L.M., O'Doherty, A., Hiripi, L., Hack, C.J., Walsh, C.P. Genomics (2004) [Pubmed]
  19. Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery. Geiman, T.M., Sankpal, U.T., Robertson, A.K., Chen, Y., Mazumdar, M., Heale, J.T., Schmiesing, J.A., Kim, W., Yokomori, K., Zhao, Y., Robertson, K.D. Nucleic Acids Res. (2004) [Pubmed]
  20. Hypomethylation and hypermethylation of DNA in Wilms tumors. Ehrlich, M., Jiang, G., Fiala, E., Dome, J.S., Yu, M.C., Long, T.I., Youn, B., Sohn, O.S., Widschwendter, M., Tomlinson, G.E., Chintagumpala, M., Champagne, M., Parham, D., Liang, G., Malik, K., Laird, P.W. Oncogene (2002) [Pubmed]
  21. The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors. Ying, J., Srivastava, G., Hsieh, W.S., Gao, Z., Murray, P., Liao, S.K., Ambinder, R., Tao, Q. Clin. Cancer Res. (2005) [Pubmed]
  22. DNMT3B interacts with hSNF2H chromatin remodeling enzyme, HDACs 1 and 2, and components of the histone methylation system. Geiman, T.M., Sankpal, U.T., Robertson, A.K., Zhao, Y., Zhao, Y., Robertson, K.D. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  23. CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Eads, C.A., Danenberg, K.D., Kawakami, K., Saltz, L.B., Danenberg, P.V., Laird, P.W. Cancer Res. (1999) [Pubmed]
  24. Reconstitution and mechanism of the stimulation of de novo methylation by human DNMT3L. Kareta, M.S., Botello, Z.M., Ennis, J.J., Chou, C., Chédin, F. J. Biol. Chem. (2006) [Pubmed]
  25. Opposite alterations of DNA methyltransferase gene expression in endometrioid and serous endometrial cancers. Xiong, Y., Dowdy, S.C., Xue, A., Shujuan, J., Eberhardt, N.L., Podratz, K.C., Jiang, S.W. Gynecol. Oncol. (2005) [Pubmed]
  26. DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes. Ehrlich, M., Buchanan, K.L., Tsien, F., Jiang, G., Sun, B., Uicker, W., Weemaes, C.M., Smeets, D., Sperling, K., Belohradsky, B.H., Tommerup, N., Misek, D.E., Rouillard, J.M., Kuick, R., Hanash, S.M. Hum. Mol. Genet. (2001) [Pubmed]
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