DNMT3B explained

DNA (cytosine-5)-methyltransferase 3 beta, is an enzyme that in humans in encoded by the DNMT3B gene. Mutation in this gene are associated with immunodeficiency, centromere instability and facial anomalies syndrome.

Function

CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase which is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes primarily to the nucleus and its expression is developmentally regulated. Eight alternatively spliced transcript variants have been described. The full length sequences of variants 4 and 5 have not been determined.^[1]

Clinical significance

Immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome is a result of defects in lymphocyte maturation resulting from aberrant DNA methylation caused by mutations in the DNMT3B gene.^[2]

Variants of the gene can also contribute to nicotine dependency.^[3]

Interactions

DNMT3B has been shown to interact with:

• CBX5,^[4]
• DNMT1,^{[4] [5]}
• DNMT3A,^{[4] [5] [6]}
• KIF4A,^[7]
• NCAPG,^[7]
• SMC2,^[7]
• SUMO1^[8] and
• UBE2I.^[8]

Further reading

• Wijmenga C, Hansen RS, Gimelli G, Björck EJ, Davies EG, Valentine D, Belohradsky BH, van Dongen JJ, Smeets DF, van den Heuvel LP, Luyten JA, Strengman E, Weemaes C, Pearson PL . Genetic variation in ICF syndrome: evidence for genetic heterogeneity . Human Mutation . 16 . 6 . 509–17 . December 2000 . 11102980 . 10.1002/1098-1004(200012)16:6<509::AID-HUMU8>3.0.CO;2-V . 6746943 . free .
• Okano M, Xie S, Li E . Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases . Nature Genetics . 19 . 3 . 219–20 . July 1998 . 9662389 . 10.1038/890 . 256263 .
• Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA . The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors . Nucleic Acids Research . 27 . 11 . 2291–8 . June 1999 . 10325416 . 148793 . 10.1093/nar/27.11.2291 .
• Xie S, Wang Z, Okano M, Nogami M, Li Y, He WW, Okumura K, Li E . Cloning, expression and chromosome locations of the human DNMT3 gene family . Gene . 236 . 1 . 87–95 . August 1999 . 10433969 . 10.1016/S0378-1119(99)00252-8 .
• Okano M, Bell DW, Haber DA, Li E . DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development . Cell . 99 . 3 . 247–57 . October 1999 . 10555141 . 10.1016/S0092-8674(00)81656-6 . 15122892 . free .
• Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM . The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome . Proceedings of the National Academy of Sciences of the United States of America . 96 . 25 . 14412–7 . December 1999 . 10588719 . 24450 . 10.1073/pnas.96.25.14412 . free . 1999PNAS...9614412H .
• Xu GL, Bestor TH, Bourc'his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Péquignot E . Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene . Nature . 402 . 6758 . 187–91 . November 1999 . 10647011 . 10.1038/46052 . 1999Natur.402..187X . 4338524 .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T . Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription . The EMBO Journal . 20 . 10 . 2536–44 . May 2001 . 11350943 . 125250 . 10.1093/emboj/20.10.2536 .
• Kang ES, Park CW, Chung JH . Dnmt3b, de novo DNA methyltransferase, interacts with SUMO-1 and Ubc9 through its N-terminal region and is subject to modification by SUMO-1 . Biochemical and Biophysical Research Communications . 289 . 4 . 862–8 . December 2001 . 11735126 . 10.1006/bbrc.2001.6057 .
• Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE, Cui H, Feinberg AP, Lengauer C, Kinzler KW, Baylin SB, Vogelstein B . DNMT1 and DNMT3b cooperate to silence genes in human cancer cells . Nature . 416 . 6880 . 552–6 . April 2002 . 11932749 . 10.1038/416552a . 2002Natur.416..552R . 4397868 .
• Hata K, Okano M, Lei H, Li E . Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice . Development . 129 . 8 . 1983–93 . April 2002 . 10.1242/dev.129.8.1983 . 11934864 .
• Beaulieu N, Morin S, Chute IC, Robert MF, Nguyen H, MacLeod AR . An essential role for DNA methyltransferase DNMT3B in cancer cell survival . The Journal of Biological Chemistry . 277 . 31 . 28176–81 . August 2002 . 12015329 . 10.1074/jbc.M204734200 . free .
• Saito Y, Kanai Y, Sakamoto M, Saito H, Ishii H, Hirohashi S . Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis . Proceedings of the National Academy of Sciences of the United States of America . 99 . 15 . 10060–5 . July 2002 . 12110732 . 126624 . 10.1073/pnas.152121799 . free . 2002PNAS...9910060S .
• Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S . Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases . The EMBO Journal . 21 . 15 . 4183–95 . August 2002 . 12145218 . 126147 . 10.1093/emboj/cdf401 .
• Deplus R, Brenner C, Burgers WA, Putmans P, Kouzarides T, de Launoit Y, Fuks F . Dnmt3L is a transcriptional repressor that recruits histone deacetylase . Nucleic Acids Research . 30 . 17 . 3831–8 . September 2002 . 12202768 . 137431 . 10.1093/nar/gkf509 .
• Shen H, Wang L, Spitz MR, Hong WK, Mao L, Wei Q . A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer . Cancer Research . 62 . 17 . 4992–5 . September 2002 . 12208751 .
• Shirohzu H, Kubota T, Kumazawa A, Sado T, Chijiwa T, Inagaki K, Suetake I, Tajima S, Wakui K, Miki Y, Hayashi M, Fukushima Y, Sasaki H . Three novel DNMT3B mutations in Japanese patients with ICF syndrome . American Journal of Medical Genetics . 112 . 1 . 31–7 . September 2002 . 12239717 . 10.1002/ajmg.10658 .

Notes and References

1. Web site: Entrez Gene: DNMT3B DNA (cytosine-5-)-methyltransferase 3 beta.
2. Ehrlich M . The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease . Clinical Immunology . 109 . 1 . 17–28 . October 2003 . 14585272 . 10.1016/S1521-6616(03)00201-8 .
3. Hancock DB, Guo Y, Reginsson GW, Gaddis NC, Lutz SM, Sherva R, Loukola A, Minica CC, Markunas CA, Han Y, Young KA, Gudbjartsson DF, Gu F, McNeil DW, Qaiser B, Glasheen C, Olson S, Landi MT, Madden PA, Farrer LA, Vink J, Saccone NL, Neale MC, Kranzler HR, McKay J, Hung RJ, Amos CI, Marazita ML, Boomsma DI, Baker TB, Gelernter J, Kaprio J, Caporaso NE, Thorgeirsson TE, Hokanson JE, Bierut LJ, Stefansson K, Johnson EO . 6 . Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence . Molecular Psychiatry . October 2017 . 23 . 9 . 1911–1919 . 28972577 . 10.1038/mp.2017.193 . 5882602 .
4. Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH . Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin . Current Biology . 13 . 14 . 1192–200 . July 2003 . 12867029 . 10.1016/s0960-9822(03)00432-9 . 2320997 . free . 2003CBio...13.1192L .
5. Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S . Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases . The EMBO Journal . 21 . 15 . 4183–95 . August 2002 . 12145218 . 126147 . 10.1093/emboj/cdf401 .
6. Ling Y, Sankpal UT, Robertson AK, McNally JG, Karpova T, Robertson KD . Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription . Nucleic Acids Research . 2004 . 32 . 2 . 598–610 . 14752048 . 373322 . 10.1093/nar/gkh195 .
7. Geiman TM, Sankpal UT, Robertson AK, Chen Y, Mazumdar M, Heale JT, Schmiesing JA, Kim W, Yokomori K, Zhao Y, Robertson KD . Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery . Nucleic Acids Research . 2004 . 32 . 9 . 2716–29 . 15148359 . 419596 . 10.1093/nar/gkh589 .
8. Kang ES, Park CW, Chung JH . Dnmt3b, de novo DNA methyltransferase, interacts with SUMO-1 and Ubc9 through its N-terminal region and is subject to modification by SUMO-1 . Biochemical and Biophysical Research Communications . 289 . 4 . 862–8 . December 2001 . 11735126 . 10.1006/bbrc.2001.6057 .