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Gene Review

Dnmt1  -  DNA methyltransferase (cytosine-5) 1

Mus musculus

Synonyms: Cxxc9, DNA (cytosine-5)-methyltransferase 1, DNA MTase MmuI, DNA methyltransferase MmuI, Dnmt, ...
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Disease relevance of Dnmt1

  • However, these same mice developed invasive T- and B-cell lymphomas earlier and at a much higher frequency than their Dnmt1 wild-type littermates [1].
  • Aging in heterozygous Dnmt1-deficient mice: effects on survival, the DNA methylation genes, and the development of amyloidosis [2].
  • Inhibitors of DNA methyltransferase (Dnmt) and histone deacetylases (HDAC) synergistically activate the methylated metallothionein I gene (MT-I) promoter in mouse lymphosarcoma cells [3].
  • It has been accepted that the mechanism of toxicity is due to the covalent binding between the DNA methyltransferase (Dnmt) and 5-aza-dC-substituted DNA [4].
  • Genes reported to be regulated by reversible methylation were not expressed ectopically or precociously in Dnmt1-deficient mouse embryos under conditions where demethylation caused biallelic expression of imprinted genes and activated transcription of endogenous retroviruses of the IAP class [5].

Psychiatry related information on Dnmt1

  • Inactivation of the DNA methyltransferase genes (Dnmt1, 3a, and 3b) was found to be lethal in mice and several human diseases (ICF and Rett syndrome) turned out to be linked to DNA methylation [6].

High impact information on Dnmt1

  • Genetic experiments have defined the importance of the DNA methyltransferase Dnmt1 for the maintenance of methylation in mouse cells and its role in neoplasia [7].
  • Cre-mediated deletion of Dnmt1 causes demethylation of cultured fibroblasts and a uniform p53-dependent cell death [8].
  • To define the mechanism through which demethylated cells die, and to establish a paradigm for identifying genes regulated by DNA methylation, we have generated mice with a conditional allele for the maintenance DNA methyltransferase gene Dnmt1 [8].
  • Our results demonstrate that loss of Dnmt1 causes cell-type-specific changes in gene expression that impinge on several pathways, including expression of imprinted genes, cell-cycle control, growth factor/receptor signal transduction and mobilization of retroelements [8].
  • Mouse oocytes and preimplantation embryos lack Dnmt1 but express a variant of this protein called Dnmt1o [9].

Chemical compound and disease context of Dnmt1

  • The major DNA cytosine methyltransferase isoform in mouse erythroleukemia cells, Dnmt1, exhibits potent dead-end inhibition with a single-stranded nucleic acid by binding to an allosteric site on the enzyme [10].
  • Dnmt1b protein purified from a baculovirus expression system was demonstrated to be a functional DNA methyltransferase, and to have Michaelis constants for both DNA and S-adenosyl-L-methionine similar to baculovirus-expressed Dnmt1 [11].
  • These results suggest that, in the presence of Dnmt1 deficiency, the effects of folate deficiency on tumor number and size may depend on the stage of adenoma development when folate deficiency is initiated [12].
  • T cells treated with procainamide, hydralazine, and other Dnmt and ERK pathway inhibitors cause lupus in mice [13].

Biological context of Dnmt1


Anatomical context of Dnmt1


Associations of Dnmt1 with chemical compounds


Enzymatic interactions of Dnmt1

  • An ODN binding site in native MTase mRNA was identified that was cleaved by endogenous RNase H with an efficiency of 85% in the extracts [25].

Regulatory relationships of Dnmt1


Other interactions of Dnmt1

  • We have compared the intrinsic susceptibilities of the imprinted region of Igf2 and H19, other imprinted genes, bulk genomic DNA, and repetitive retroviral sequences to Dnmt1 overexpression [16].
  • Therefore, Dnmt1 and Dnmt3a/3b share targets in CpG islands [28].
  • To elucidate how DNA methyltransferases (Dnmts) participate in methylation of the genomic components, we investigated the genome-wide DNA methylation pattern of the T-DMRs with Dnmt1-, Dnmt3a-, and/or Dnmt3b-deficient ES cells by restriction landmark genomic scanning (RLGS) [28].
  • The reduced Dnmt1 mRNA and protein were accompanied by increased reelin mRNA expression [14].
  • Mouse Dnmt1 is a 180 kDa protein comprising the N-terminal regulatory domain, which covers 2/3 of the molecule, and the rest C-terminal catalytic domain [29].

Analytical, diagnostic and therapeutic context of Dnmt1


  1. DNA methyltransferase deficiency modifies cancer susceptibility in mice lacking DNA mismatch repair. Trinh, B.N., Long, T.I., Nickel, A.E., Shibata, D., Laird, P.W. Mol. Cell. Biol. (2002) [Pubmed]
  2. Aging in heterozygous Dnmt1-deficient mice: effects on survival, the DNA methylation genes, and the development of amyloidosis. Ray, D., Wu, A., Wilkinson, J.E., Murphy, H.S., Lu, Q., Kluve-Beckerman, B., Liepnieks, J.J., Benson, M., Yung, R., Richardson, B. J. Gerontol. A Biol. Sci. Med. Sci. (2006) [Pubmed]
  3. Inhibitors of histone deacetylase and DNA methyltransferase synergistically activate the methylated metallothionein I promoter by activating the transcription factor MTF-1 and forming an open chromatin structure. Ghoshal, K., Datta, J., Majumder, S., Bai, S., Dong, X., Parthun, M., Jacob, S.T. Mol. Cell. Biol. (2002) [Pubmed]
  4. De novo DNA methyltransferases Dnmt3a and Dnmt3b primarily mediate the cytotoxic effect of 5-aza-2'-deoxycytidine. Oka, M., Meacham, A.M., Hamazaki, T., Rodić, N., Chang, L.J., Terada, N. Oncogene (2005) [Pubmed]
  5. Cytosine methylation and mammalian development. Walsh, C.P., Bestor, T.H. Genes Dev. (1999) [Pubmed]
  6. DNA methylation, nuclear structure, gene expression and cancer. Leonhardt, H., Cardoso, M.C. J. Cell. Biochem. Suppl. (2000) [Pubmed]
  7. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Robert, M.F., Morin, S., Beaulieu, N., Gauthier, F., Chute, I.C., Barsalou, A., MacLeod, A.R. Nat. Genet. (2003) [Pubmed]
  8. Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Jackson-Grusby, L., Beard, C., Possemato, R., Tudor, M., Fambrough, D., Csankovszki, G., Dausman, J., Lee, P., Wilson, C., Lander, E., Jaenisch, R. Nat. Genet. (2001) [Pubmed]
  9. Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Howell, C.Y., Bestor, T.H., Ding, F., Latham, K.E., Mertineit, C., Trasler, J.M., Chaillet, J.R. Cell (2001) [Pubmed]
  10. A potent cell-active allosteric inhibitor of murine DNA cytosine C5 methyltransferase. Flynn, J., Fang, J.Y., Mikovits, J.A., Reich, N.O. J. Biol. Chem. (2003) [Pubmed]
  11. Characterization of the human DNA methyltransferase splice variant Dnmt1b. Bonfils, C., Beaulieu, N., Chan, E., Cotton-Montpetit, J., MacLeod, A.R. J. Biol. Chem. (2000) [Pubmed]
  12. Impact of Dnmt1 deficiency, with and without low folate diets, on tumor numbers and DNA methylation in Min mice. Trasler, J., Deng, L., Melnyk, S., Pogribny, I., Hiou-Tim, F., Sibani, S., Oakes, C., Li, E., James, S.J., Rozen, R. Carcinogenesis (2003) [Pubmed]
  13. Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. Lu, Q., Wu, A., Richardson, B.C. J. Immunol. (2005) [Pubmed]
  14. DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. Noh, J.S., Sharma, R.P., Veldic, M., Salvacion, A.A., Jia, X., Chen, Y., Costa, E., Guidotti, A., Grayson, D.R. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  15. Recruitment of DNA methyltransferase I to DNA repair sites. Mortusewicz, O., Schermelleh, L., Walter, J., Cardoso, M.C., Leonhardt, H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  16. Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Biniszkiewicz, D., Gribnau, J., Ramsahoye, B., Gaudet, F., Eggan, K., Humpherys, D., Mastrangelo, M.A., Jun, Z., Walter, J., Jaenisch, R. Mol. Cell. Biol. (2002) [Pubmed]
  17. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Tsumura, A., Hayakawa, T., Kumaki, Y., Takebayashi, S., Sakaue, M., Matsuoka, C., Shimotohno, K., Ishikawa, F., Li, E., Ueda, H.R., Nakayama, J., Okano, M. Genes Cells (2006) [Pubmed]
  18. Genomic imprinting and epigenetic reprogramming: unearthing the garden of forking paths. Kierszenbaum, A.L. Mol. Reprod. Dev. (2002) [Pubmed]
  19. Deregulation of DNA methyltransferases and loss of parental methylation at the insulin-like growth factor II (Igf2)/H19 loci in p53 knockout mice prior to tumor development. Park, I.Y., Sohn, B.H., Choo, J.H., Joe, C.O., Seong, J.K., Lee, Y.I., Chung, J.H. J. Cell. Biochem. (2005) [Pubmed]
  20. Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways. Kimura, H., Nakamura, T., Ogawa, T., Tanaka, S., Shiota, K. Nucleic Acids Res. (2003) [Pubmed]
  21. Stage-by-stage change in DNA methylation status of Dnmt1 locus during mouse early development. Ko, Y.G., Nishino, K., Hattori, N., Arai, Y., Tanaka, S., Shiota, K. J. Biol. Chem. (2005) [Pubmed]
  22. Biochemical fractionation reveals association of DNA methyltransferase (Dnmt) 3b with Dnmt1 and that of Dnmt 3a with a histone H3 methyltransferase and Hdac1. Datta, J., Ghoshal, K., Sharma, S.M., Tajima, S., Jacob, S.T. J. Cell. Biochem. (2003) [Pubmed]
  23. PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA. Iida, T., Suetake, I., Tajima, S., Morioka, H., Ohta, S., Obuse, C., Tsurimoto, T. Genes Cells (2002) [Pubmed]
  24. A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. Yoder, J.A., Bestor, T.H. Hum. Mol. Genet. (1998) [Pubmed]
  25. Rapid determination and quantitation of the accessibility to native RNAs by antisense oligodeoxynucleotides in murine cell extracts. Scherr, M., Rossi, J.J. Nucleic Acids Res. (1998) [Pubmed]
  26. DNA methylation is a nonredundant repressor of the Th2 effector program. Makar, K.W., Wilson, C.B. J. Immunol. (2004) [Pubmed]
  27. Dynamics of Dnmt1 methyltransferase expression and intracellular localization during oogenesis and preimplantation development. Ratnam, S., Mertineit, C., Ding, F., Howell, C.Y., Clarke, H.J., Bestor, T.H., Chaillet, J.R., Trasler, J.M. Dev. Biol. (2002) [Pubmed]
  28. Preference of DNA methyltransferases for CpG islands in mouse embryonic stem cells. Hattori, N., Abe, T., Hattori, N., Suzuki, M., Matsuyama, T., Yoshida, S., Li, E., Shiota, K. Genome Res. (2004) [Pubmed]
  29. The Amino-Terminus of Mouse DNA Methyltransferase 1 Forms an Independent Domain and Binds to DNA with the Sequence Involving PCNA Binding Motif. Suetake, I., Hayata, D., Tajima, S. J. Biochem. (2006) [Pubmed]
  30. Differential expression of DNA-methyltransferases in drug resistant murine neuroblastoma cells. Qiu, Y.Y., Mirkin, B.L., Dwivedi, R.S. Cancer Detect. Prev. (2002) [Pubmed]
  31. Neonatal exposure to diethylstilbestrol alters the expression of DNA methyltransferases and methylation of genomic DNA in the epididymis of mice. Sato, K., Fukata, H., Kogo, Y., Ohgane, J., Shiota, K., Mori, C. Endocr. J. (2006) [Pubmed]
  32. p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding. Peterson, E.J., Bögler, O., Taylor, S.M. Cancer Res. (2003) [Pubmed]
  33. Expression of an alternative Dnmt1 isoform during muscle differentiation. Aguirre-Arteta, A.M., Grunewald, I., Cardoso, M.C., Leonhardt, H. Cell Growth Differ. (2000) [Pubmed]
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