DNMT1

DNA (cytosine-5)-methyltransferase 1 is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. In humans, it is encoded by the DNMT1 gene.[5] DNMT1 forms part of the family of DNA methyltransferase enzymes, which consists primarily of DNMT1, DNMT3A, and DNMT3B.

DNMT1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4YOC, 3EPZ, 3PTA, 3SWR, 4WXX
Identifiers
Aliases	DNMT1, ADCADN, AIM, CXXC9, DNMT, HSN1E, MCMT, m.HsaI, DNA (cytosine-5-)-methyltransferase 1, DNA methyltransferase 1
External IDs	OMIM: 126375 MGI: 94912 HomoloGene: 124071 GeneCards: DNMT1
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.2 Start 10,133,345 bp[1] End 10,231,286 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 A3|9 7.66 cM Start 20,907,209 bp[2] End 20,959,888 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • methyltransferase activity • DNA binding • transferase activity • promoter-specific chromatin binding • methyl-CpG binding • zinc ion binding • DNA-methyltransferase activity • chromatin binding • metal ion binding • GO:0001948 protein binding • RNA binding • DNA (cytosine-5-)-methyltransferase activity • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • pericentric heterochromatin • replication fork • nucleoplasm • heterochromatin • cell nucleus Biological process • gene silencing • C-5 methylation of cytosine • regulation of transcription, DNA-templated • maintenance of DNA methylation • positive regulation of methylation-dependent chromatin silencing • negative regulation of transcription from RNA polymerase II promoter • transcription, DNA-templated • methylation • DNA methylation • positive regulation of gene expression • negative regulation of gene expression, epigenetic • positive regulation of histone H3-K4 methylation • regulation of cell proliferation • negative regulation of histone H3-K9 methylation • cellular response to amino acid stimulus • regulation of gene expression • Ras protein signal transduction • negative regulation of transcription, DNA-templated • covalent chromatin modification • DNA methylation on cytosine • DNA methylation involved in embryo development • chromatin organization • DNA methylation on cytosine within a CG sequence • negative regulation of gene expression • positive regulation of vascular smooth muscle cell proliferation • negative regulation of vascular associated smooth muscle cell apoptotic process • negative regulation of vascular smooth muscle cell differentiation involved in phenotypic switching Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1786	13433
Ensembl	ENSG00000130816	ENSMUSG00000004099
UniProt	P26358	P13864
RefSeq (mRNA)	NM_001130823 NM_001379 NM_001318730 NM_001318731	NM_001199431 NM_001199432 NM_001199433 NM_010066 NM_001314011
RefSeq (protein)	NP_001124295 NP_001305659 NP_001305660 NP_001370	NP_001186360 NP_001186361 NP_001186362 NP_001300940 NP_034196
Location (UCSC)	Chr 19: 10.13 – 10.23 Mb	Chr 9: 20.91 – 20.96 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

This enzyme is responsible for maintenance DNA methylation which ensures the fidelity of replication of inherited epigenetic patterns. It has a very distinguishable preference of methylating CpGs on hemimethylated DNA.[6] Aberrant methylation patterns are associated with certain human tumors and developmental abnormalities.[7][8]

See also

• DNA methyltransferase

Interactions

DNMT1 has been shown to interact with UHRF1,:

• DMAP1,[9]
• DNMT3A[10]
• DNMT3B,[10][11]
• HDAC2,[9]
• PCNA,[9][12][13]
• RB1.[14] and
• G9A[15]

DNMT1 is highly transcribed during the S phase of the cell cycle when it is required for methylation of the newly generated hemimethylated sites on daughter DNA strands.[16] Its interaction with PCNA and UHRF1 has been implicated in localizing it to the replication fork.[17] The direct co-operation between DNMT1 and G9a coordinates DNA and H3K9 methylation during cell division.[15] This chromatin methylation is necessary for stable repression of gene expression during mammalian development.

Model organisms

Knockout experiments have shown that this enzyme is responsible for the bulk of methylation in mouse cells, and it is essential for embryonic development.[18] It has also been shown that a lack of both maternal and zygotic Dnmt1 results in complete demethylation of imprinted genes in blastocysts.[19]

Clinical significance

DNMT1 plays a critical role in Hematopoietic stem cell (HSC) maintenance. HSCs with reduced DNMT1 fail to self-renew efficiently post-transplantation.[20] It has also been shown to be critical for other stem cell types such as Intestinal stem cells (ISCs) and Mammary stem cells (MaSCs). Conditional deletion of DNMT1 results in overall intestinal hypomethylation, crypt expansion and altered differentiation timing of ISCs, and proliferation and maintenance of MaSCs.[21]

References

1. GRCh38: Ensembl release 89: ENSG00000130816 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000004099 - 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. Yen RW, Vertino PM, Nelkin BD, Yu JJ, el-Deiry W, Cumaraswamy A, Lennon GG, Trask BJ, Celano P, Baylin SB (May 1992). "Isolation and characterization of the cDNA encoding human DNA methyltransferase". Nucleic Acids Research. 20 (9): 2287–91. doi:10.1093/nar/20.9.2287. PMC 312343. PMID 1594447.
6. Hermann A, Goyal R, Jeltsch A (November 2004). "The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites". The Journal of Biological Chemistry. 279 (46): 48350–9. doi:10.1074/jbc.M403427200. PMID 15339928.
7. Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA, Hammans S, Hojo K, Yamanishi H, Karpf AR, Wallace DC, Simon M, Lander C, Boardman LA, Cunningham JM, Smith GE, Litchy WJ, Boes B, Atkinson EJ, Middha S, B Dyck PJ, Parisi JE, Mer G, Smith DI, Dyck PJ (June 2011). "Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss". Nature Genetics. 43 (6): 595–600. doi:10.1038/ng.830. PMC 3102765. PMID 21532572.
8. "Entrez Gene: DNMT1 DNA (cytosine-5-)-methyltransferase 1".
9. Rountree MR, Bachman KE, Baylin SB (July 2000). "DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci". Nature Genetics. 25 (3): 269–77. doi:10.1038/77023. PMID 10888872.
10. Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S (August 2002). "Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases". The EMBO Journal. 21 (15): 4183–95. doi:10.1093/emboj/cdf401. PMC 126147. PMID 12145218.
11. Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH (July 2003). "Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin". Current Biology. 13 (14): 1192–200. doi:10.1016/s0960-9822(03)00432-9. PMID 12867029.
12. Iida T, Suetake I, Tajima S, Morioka H, Ohta S, Obuse C, Tsurimoto T (October 2002). "PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA". Genes to Cells. 7 (10): 997–1007. doi:10.1046/j.1365-2443.2002.00584.x. PMID 12354094.
13. Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF (September 1997). "Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1". Science. 277 (5334): 1996–2000. doi:10.1126/science.277.5334.1996. PMID 9302295.
14. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP (July 2000). "DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters". Nature Genetics. 25 (3): 338–42. doi:10.1038/77124. PMID 10888886.
15. Estève PO, Chin HG, Smallwood A, Feehery GR, Gangisetty O, Karpf AR, Carey MF, Pradhan S (November 2006). "Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication". Genes & Development. 20 (22): 3089–103. doi:10.1101/gad.1463706. PMC 1635145. PMID 17085482.
16. Robertson KD, Keyomarsi K, Gonzales FA, Velicescu M, Jones PA (May 2000). "Differential mRNA expression of the human DNA methyltransferases (DNMTs) 1, 3a and 3b during the G(0)/G(1) to S phase transition in normal and tumor cells". Nucleic Acids Research. 28 (10): 2108–13. doi:10.1093/nar/28.10.2108. PMC 105379. PMID 10773079.
17. Jones PA, Liang G (November 2009). "Rethinking how DNA methylation patterns are maintained". Nature Reviews. Genetics. 10 (11): 805–11. doi:10.1038/nrg2651. PMC 2848124. PMID 19789556.
18. Li E, Bestor TH, Jaenisch R (June 1992). "Targeted mutation of the DNA methyltransferase gene results in embryonic lethality". Cell. 69 (6): 915–26. doi:10.1016/0092-8674(92)90611-F. PMID 1606615.
19. Hirasawa R, Chiba H, Kaneda M, Tajima S, Li E, Jaenisch R, Sasaki H (June 2008). "Maternal and zygotic Dnmt1 are necessary and sufficient for the maintenance of DNA methylation imprints during preimplantation development". Genes & Development. 22 (12): 1607–16. doi:10.1101/gad.1667008. PMC 2428059. PMID 18559477.
20. Trowbridge JJ, Snow JW, Kim J, Orkin SH (October 2009). "DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells". Cell Stem Cell. 5 (4): 442–9. doi:10.1016/j.stem.2009.08.016. PMC 2767228. PMID 19796624.
21. Avgustinova A, Benitah SA (October 2016). "Epigenetic control of adult stem cell function". Nature Reviews. Molecular Cell Biology. 17 (10): 643–58. doi:10.1038/nrm.2016.76. PMID 27405257.

Further reading

• Smith SS, Kaplan BE, Sowers LC, Newman EM (May 1992). "Mechanism of human methyl-directed DNA methyltransferase and the fidelity of cytosine methylation". Proceedings of the National Academy of Sciences of the United States of America. 89 (10): 4744–8. doi:10.1073/pnas.89.10.4744. PMC 49160. PMID 1584813.
• Bestor T, Laudano A, Mattaliano R, Ingram V (October 1988). "Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases". Journal of Molecular Biology. 203 (4): 971–83. doi:10.1016/0022-2836(88)90122-2. PMID 3210246.
• Smith SS (1994). "Biological implications of the mechanism of action of human DNA (cytosine-5)methyltransferase". Progress in Nucleic Acid Research and Molecular Biology. 49: 65–111. doi:10.1016/S0079-6603(08)60048-3. ISBN 9780125400497. PMID 7863011.
• Hijmans EM, Voorhoeve PM, Beijersbergen RL, van 't Veer LJ, Bernards R (June 1995). "E2F-5, a new E2F family member that interacts with p130 in vivo". Molecular and Cellular Biology. 15 (6): 3082–9. doi:10.1128/mcb.15.6.3082. PMC 230539. PMID 7760804.
• Yoder JA, Yen RW, Vertino PM, Bestor TH, Baylin SB (December 1996). "New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase". The Journal of Biological Chemistry. 271 (49): 31092–7. doi:10.1074/jbc.271.49.31092. PMID 8940105.
• Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF (September 1997). "Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1". Science. 277 (5334): 1996–2000. doi:10.1126/science.277.5334.1996. PMID 9302295.
• Kho MR, Baker DJ, Laayoun A, Smith SS (January 1998). "Stalling of human DNA (cytosine-5) methyltransferase at single-strand conformers from a site of dynamic mutation". Journal of Molecular Biology. 275 (1): 67–79. doi:10.1006/jmbi.1997.1430. PMID 9451440.
• Baylin SB (September 1997). "Tying it all together: epigenetics, genetics, cell cycle, and cancer". Science. 277 (5334): 1948–9. doi:10.1126/science.277.5334.1948. PMID 9333948.
• Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA (June 1999). "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. doi:10.1093/nar/27.11.2291. PMC 148793. PMID 10325416.
• Michaelson JS, Bader D, Kuo F, Kozak C, Leder P (August 1999). "Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development". Genes & Development. 13 (15): 1918–23. doi:10.1101/gad.13.15.1918. PMC 316925. PMID 10444590.
• Hsu DW, Lin MJ, Lee TL, Wen SC, Chen X, Shen CK (August 1999). "Two major forms of DNA (cytosine-5) methyltransferase in human somatic tissues". Proceedings of the National Academy of Sciences of the United States of America. 96 (17): 9751–6. doi:10.1073/pnas.96.17.9751. PMC 22282. PMID 10449766.
• Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T (January 2000). "DNA methyltransferase Dnmt1 associates with histone deacetylase activity". Nature Genetics. 24 (1): 88–91. doi:10.1038/71750. PMID 10615135.
• Bonfils C, Beaulieu N, Chan E, Cotton-Montpetit J, MacLeod AR (April 2000). "Characterization of the human DNA methyltransferase splice variant Dnmt1b". The Journal of Biological Chemistry. 275 (15): 10754–60. doi:10.1074/jbc.275.15.10754. PMID 10753866.
• Rountree MR, Bachman KE, Baylin SB (July 2000). "DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci". Nature Genetics. 25 (3): 269–77. doi:10.1038/77023. PMID 10888872.
• Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP (July 2000). "DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters". Nature Genetics. 25 (3): 338–42. doi:10.1038/77124. PMID 10888886.
• Tatematsu KI, Yamazaki T, Ishikawa F (August 2000). "MBD2-MBD3 complex binds to hemi-methylated DNA and forms a complex containing DNMT1 at the replication foci in late S phase". Genes to Cells. 5 (8): 677–88. doi:10.1046/j.1365-2443.2000.00359.x. PMID 10947852.
• Mizuno S, Chijiwa T, Okamura T, Akashi K, Fukumaki Y, Niho Y, Sasaki H (March 2001). "Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia". Blood. 97 (5): 1172–9. doi:10.1182/blood.V97.5.1172. PMID 11222358.
• Fatemi M, Hermann A, Pradhan S, Jeltsch A (June 2001). "The activity of the murine DNA methyltransferase Dnmt1 is controlled by interaction of the catalytic domain with the N-terminal part of the enzyme leading to an allosteric activation of the enzyme after binding to methylated DNA". Journal of Molecular Biology. 309 (5): 1189–99. doi:10.1006/jmbi.2001.4709. PMID 11399088.
• Dintilhac A, Bernués J (March 2002). "HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences". The Journal of Biological Chemistry. 277 (9): 7021–8. doi:10.1074/jbc.M108417200. PMID 11748221.
• Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S, Pelicci PG (February 2002). "Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor". Science. 295 (5557): 1079–82. doi:10.1126/science.1065173. PMID 11834837.
• Pradhan S, Kim GD (February 2002). "The retinoblastoma gene product interacts with maintenance human DNA (cytosine-5) methyltransferase and modulates its activity". The EMBO Journal. 21 (4): 779–88. doi:10.1093/emboj/21.4.779. PMC 125847. PMID 11847125.
• Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE, Cui H, Feinberg AP, Lengauer C, Kinzler KW, Baylin SB, Vogelstein B (April 2002). "DNMT1 and DNMT3b cooperate to silence genes in human cancer cells". Nature. 416 (6880): 552–6. doi:10.1038/416552a. PMID 11932749.
• Jair KW, Bachman KE, Suzuki H, Ting AH, Rhee I, Yen RW, Baylin SB, Schuebel KE (January 2006). "De novo CpG island methylation in human cancer cells". Cancer Research. 66 (2): 682–92. doi:10.1158/0008-5472.CAN-05-1980. PMID 16423997.
• Ting AH, Jair KW, Schuebel KE, Baylin SB (January 2006). "Differential requirement for DNA methyltransferase 1 in maintaining human cancer cell gene promoter hypermethylation". Cancer Research. 66 (2): 729–35. doi:10.1158/0008-5472.CAN-05-1537. PMID 16424002.
• Svedruzić ZM (2008). "Mammalian cytosine DNA methyltransferase Dnmt1: enzymatic mechanism, novel mechanism-based inhibitors, and RNA-directed DNA methylation" (PDF). Current Medicinal Chemistry. 15 (1): 92–106. doi:10.2174/092986708783330700. PMID 18220765.
• Bestor T, Laudano A, Mattaliano R, Ingram V (October 1988). "Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases". Journal of Molecular Biology. 203 (4): 971–83. doi:10.1016/0022-2836(88)90122-2. PMID 3210246.

External links

• GeneReviews/NCBI/NIH/UW entry on DNMT1-Related Dementia, Deafness, and Sensory Neuropathy