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DNMT1  -  DNA (cytosine-5-)-methyltransferase 1

Homo sapiens

 
 
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Disease relevance of DNMT1

 

Psychiatry related information on DNMT1

  • In BA9 of SZ and bipolar disorder patients with psychosis, DNMT1 mRNA and protein expression preferentially increases in layer I, II, and IV interneurons, and this increase is paralleled by a decreased number of GAD67 mRNA-positive neurons [5].
  • Body temperature, locomotor activity, skilled paw-reaching ability and performance of the delayed non-match to place (DNMTP) procedure was assessed daily during this period and on an intermittent schedule over the following 16 days [6].
  • (a) The operant delayed non-matching-to-position (DNMTP) test was used to study short-term memory function [7].
 

High impact information on DNMT1

  • CpG island hypermethylation is maintained in human colorectal cancer cells after RNAi-mediated depletion of DNMT1 [8].
  • In human bladder cancer cells, selective depletion of DNMT1 with antisense inhibitors has been shown to induce demethylation and reactivation of the silenced tumor-suppressor gene CDKN2A [9].
  • DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells [9].
  • Selective depletion of DNMT1 using either antisense or siRNA resulted in lower cellular maintenance methyltransferase activity, global and gene-specific demethylation and re-expression of tumor-suppressor genes in human cancer cells [9].
  • We show here that the chief enzyme that maintains mammalian DNA methylation, DNMT1, can also establish a repressive transcription complex [10].
 

Chemical compound and disease context of DNMT1

 

Biological context of DNMT1

  • Thus, DNMT1 not only maintains DNA methylation, but also may directly target, in a heritable manner, transcriptionally repressive chromatin to the genome during DNA replication [10].
  • These data suggest that overexpression of DNMT1 and DNMT3a, DNA hypermethylation on CpG islands, and DNA hypomethylation on pericentromeric satellite regions are early events during hepatocarcinogenesis, and that reduced expression of MBD4 may play a role in malignant progression of HCC [4].
  • The synergistic activation of ER occurs concomitantly with markedly reduced soluble DNMT1 expression and activity, partial demethylation of the ER CpG island, and increased acetylation of histones H(3) and H(4) [13].
  • In adenomatous polyps, although DNMT1 expression coincided with the expression of other cell proliferation markers, many DNMT1-expressing cells also expressed p21 [3].
  • DNMT1 overexpression correlated significantly with poorer tumor differentiation (P < 0.001), but not with the phenotype (gastric type versus intestinal type) of the cancer cells [16].
 

Anatomical context of DNMT1

  • Treatment with pharmacologic grade DNMT1 anti-sense oligonucleotides and STAT3 small-interfering RNA induces in the malignant T cells DNA demethylation and expression of SHP-1 gene [17].
  • In AML, 5.3-, 4.4-, and 11.7-fold mean increases were seen in the levels of DNMT1, 3A, and 3B, respectively, compared with the control bone marrow cells [1].
  • The rDNA primary transcript level was significantly elevated in DNMT1-/- or DNMT3B-/- human colon carcinoma (HCT116) cells [18].
  • Therefore, DNMT1 expression relative to proliferation was investigated in TCC cell lines and tissue as well as in renal carcinoma (RCC) cell lines, which also display hypomethylation, as indicated by decreased LINE-1 methylation [19].
  • DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas [20].
 

Associations of DNMT1 with chemical compounds

 

Physical interactions of DNMT1

  • Moreover, by a co-immunoprecipitation experiment, DNMT1 was shown to form a complex with MBD2 and MBD3 [24].
  • Both Daxx and DMAP1 formed a complex with DNMT1 and colocalized in the nucleus [25].
  • Here, DNMT1 is shown to bind p53 and colocalize in the nucleus [26].
  • CONCLUSIONS: Elevated mRNA expression of DNMT1 may be an independent prognostic factor in NSCLC and CpG island hypermethylation in NSCLC may be maintained by a complex interaction of several factors rather than by a simple transcriptional up-regulation of DNMT1 [27].
  • We find that SUV39H1 also binds to Dnmt1 and, consistent with these interactions, SUV39H1 can purify DNA methyltransferase activity from nuclear extracts [28].
 

Enzymatic interactions of DNMT1

 

Regulatory relationships of DNMT1

  • We hypothesize that MBD2 enzyme activity is repressed and that DNMT1 enzyme activity is elevated in human prostate cancer [30].
  • These results demonstrate that the methylated and unmethylated MT-I promoter are differentially regulated by DNA methyltransferase and methyl-CpG binding proteins, and DNMT1 could suppress MT promoter by a transcriptional mechanism independent of its enzymatic function [23].
  • DNMT1-mediated methylation is stimulated by p53 in vitro [26].
  • Human DNA methyltransferase gene DNMT1 is regulated by the APC pathway [31].
  • DNMT1 levels are regulated with the cell cycle and are induced upon entry into the S phase of the cell cycle [32].
 

Other interactions of DNMT1

 

Analytical, diagnostic and therapeutic context of DNMT1

References

  1. 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]
  2. Methyl-CpG-binding domain protein-2 mediates transcriptional repression associated with hypermethylated GSTP1 CpG islands in MCF-7 breast cancer cells. Lin, X., Nelson, W.G. Cancer Res. (2003) [Pubmed]
  3. Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis. De Marzo, A.M., Marchi, V.L., Yang, E.S., Veeraswamy, R., Lin, X., Nelson, W.G. Cancer Res. (1999) [Pubmed]
  4. Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis. Saito, Y., Kanai, Y., Sakamoto, M., Saito, H., Ishii, H., Hirohashi, S. Hepatology (2001) [Pubmed]
  5. In psychosis, cortical interneurons overexpress DNA-methyltransferase 1. Veldic, M., Guidotti, A., Maloku, E., Davis, J.M., Costa, E. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. Behavioural analysis of the acute and chronic effects of MDMA treatment in the rat. Marston, H.M., Reid, M.E., Lawrence, J.A., Olverman, H.J., Butcher, S.P. Psychopharmacology (Berl.) (1999) [Pubmed]
  7. Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats. De Bruin, N.M., Kiliaan, A.J., De Wilde, M.C., Broersen, L.M. Neurobiology of learning and memory. (2003) [Pubmed]
  8. CpG island hypermethylation is maintained in human colorectal cancer cells after RNAi-mediated depletion of DNMT1. Ting, A.H., Jair, K.W., Suzuki, H., Yen, R.W., Baylin, S.B., Schuebel, K.E. Nat. Genet. (2004) [Pubmed]
  9. 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]
  10. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Rountree, M.R., Bachman, K.E., Baylin, S.B. Nat. Genet. (2000) [Pubmed]
  11. Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells. Kassis, E.S., Zhao, M., Hong, J.A., Chen, G.A., Nguyen, D.M., Schrump, D.S. J. Thorac. Cardiovasc. Surg. (2006) [Pubmed]
  12. DNA methylation in ovarian cancer. II. Expression of DNA methyltransferases in ovarian cancer cell lines and normal ovarian epithelial cells. Ahluwalia, A., Hurteau, J.A., Bigsby, R.M., Nephew, K.P. Gynecol. Oncol. (2001) [Pubmed]
  13. Synergistic activation of functional estrogen receptor (ER)-alpha by DNA methyltransferase and histone deacetylase inhibition in human ER-alpha-negative breast cancer cells. Yang, X., Phillips, D.L., Ferguson, A.T., Nelson, W.G., Herman, J.G., Davidson, N.E. Cancer Res. (2001) [Pubmed]
  14. Mitoxantrone mediates demethylation and reexpression of cyclin d2, estrogen receptor and 14.3.3sigma in breast cancer cells. Parker, B.S., Cutts, S.M., Nudelman, A., Rephaeli, A., Phillips, D.R., Sukumar, S. Cancer Biol. Ther. (2003) [Pubmed]
  15. Optimizing therapy with methylation inhibitors in myelodysplastic syndromes: dose, duration, and patient selection. Issa, J.P. Nature clinical practice. Oncology. (2005) [Pubmed]
  16. Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. Etoh, T., Kanai, Y., Ushijima, S., Nakagawa, T., Nakanishi, Y., Sasako, M., Kitano, S., Hirohashi, S. Am. J. Pathol. (2004) [Pubmed]
  17. STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Zhang, Q., Wang, H.Y., Marzec, M., Raghunath, P.N., Nagasawa, T., Wasik, M.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  18. 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]
  19. Decrease of DNA methyltransferase 1 expression relative to cell proliferation in transitional cell carcinoma. Kimura, F., Seifert, H.H., Florl, A.R., Santourlidis, S., Steinhoff, C., Swiatkowski, S., Mahotka, C., Gerharz, C.D., Schulz, W.A. Int. J. Cancer (2003) [Pubmed]
  20. DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. Peng, D.F., Kanai, Y., Sawada, M., Ushijima, S., Hiraoka, N., Kitazawa, S., Hirohashi, S. Carcinogenesis (2006) [Pubmed]
  21. 5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Ghoshal, K., Datta, J., Majumder, S., Bai, S., Kutay, H., Motiwala, T., Jacob, S.T. Mol. Cell. Biol. (2005) [Pubmed]
  22. DNA damage-induced down-regulation of human Cdc25C and Cdc2 is mediated by cooperation between p53 and maintenance DNA (cytosine-5) methyltransferase 1. Le Gac, G., Estève, P.O., Ferec, C., Pradhan, S. J. Biol. Chem. (2006) [Pubmed]
  23. Epigenetic regulation of metallothionein-i gene expression: differential regulation of methylated and unmethylated promoters by DNA methyltransferases and methyl CpG binding proteins. Majumder, S., Kutay, H., Datta, J., Summers, D., Jacob, S.T., Ghoshal, K. J. Cell. Biochem. (2006) [Pubmed]
  24. MBD2-MBD3 complex binds to hemi-methylated DNA and forms a complex containing DNMT1 at the replication foci in late S phase. Tatematsu, K.I., Yamazaki, T., Ishikawa, F. Genes Cells (2000) [Pubmed]
  25. Physical and functional interactions between Daxx and DNA methyltransferase 1-associated protein, DMAP1. Muromoto, R., Sugiyama, K., Takachi, A., Imoto, S., Sato, N., Yamamoto, T., Oritani, K., Shimoda, K., Matsuda, T. J. Immunol. (2004) [Pubmed]
  26. Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters. Estève, P.O., Chin, H.G., Pradhan, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  27. Elevated mRNA levels of DNA methyltransferase-1 as an independent prognostic factor in primary nonsmall cell lung cancer. Kim, H., Kwon, Y.M., Kim, J.S., Han, J., Shim, Y.M., Park, J., Kim, D.H. Cancer (2006) [Pubmed]
  28. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Fuks, F., Hurd, P.J., Deplus, R., Kouzarides, T. Nucleic Acids Res. (2003) [Pubmed]
  29. De novo CpG island methylation in human cancer cells. Jair, K.W., Bachman, K.E., Suzuki, H., Ting, A.H., Rhee, I., Yen, R.W., Baylin, S.B., Schuebel, K.E. Cancer Res. (2006) [Pubmed]
  30. DNA methyltransferase and demethylase in human prostate cancer. Patra, S.K., Patra, A., Zhao, H., Dahiya, R. Mol. Carcinog. (2002) [Pubmed]
  31. Human DNA methyltransferase gene DNMT1 is regulated by the APC pathway. Campbell, P.M., Szyf, M. Carcinogenesis (2003) [Pubmed]
  32. Regulation of the DNA methylation machinery and its role in cellular transformation. Szyf, M., Detich, N. Prog. Nucleic Acid Res. Mol. Biol. (2001) [Pubmed]
  33. 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]
  34. Sex-specific windows for high mRNA expression of DNA methyltransferases 1 and 3A and methyl-CpG-binding domain proteins 2 and 4 in human fetal gonads. Galetzka, D., Weis, E., Tralau, T., Seidmann, L., Haaf, T. Mol. Reprod. Dev. (2007) [Pubmed]
  35. DNA methylation status of hMLH1, p16(INK4a), and CDH1 is not associated with mRNA expression levels of DNA methyltransferase and DNA demethylase in gastric carcinomas. Oue, N., Kuraoka, K., Kuniyasu, H., Yokozaki, H., Wakikawa, A., Matsusaki, K., Yasui, W. Oncol. Rep. (2001) [Pubmed]
 
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