DNMT1 explained

DNA (cytosine-5)-methyltransferase 1 (Dnmt1) is an enzyme that catalyzes the transfer of methyl groups to specific CpG sites in DNA, a process called DNA methylation. In humans, it is encoded by the DNMT1 gene.^[1] Dnmt1 forms part of the family of DNA methyltransferase enzymes, which consists primarily of DNMT1, DNMT3A, and DNMT3B.

Function

This enzyme is responsible for maintaining DNA methylation, which ensures the fidelity of this epigenetic patterns across cell divisions. In line with this role, it has a strong preference towards methylating CpGs on hemimethylated DNA.^[2] However, DNMT1 can catalyze de novo DNA methylation in specific genomic contexts, including transposable elements and paternal imprint control regions.^{[3] [4]} Aberrant methylation patterns are associated with certain human tumors and developmental abnormalities.^{[5] [6]}

See also

• DNA methyltransferase

Interactions

DNMT1 has been shown to interact with UHRF1,:

• DMAP1,
• DNMT3A^[7]
• DNMT3B,^{[7] [8]}
• HDAC2,^[9]
• PCNA,^{[9] [10] [11]}
• RB1.^[12] and
• G9A^[13]

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.^[14] Its interaction with PCNA and UHRF1 has been implicated in localizing it to the replication fork.^[15] The direct co-operation between DNMT1 and G9a coordinates DNA and H3K9 methylation during cell division. 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.^[16] It has also been shown that a lack of both maternal and zygotic Dnmt1 results in complete demethylation of imprinted genes in blastocysts.^[17]

Clinical significance

DNMT1 plays a critical role in Hematopoietic stem cell (HSC) maintenance. HSCs with reduced DNMT1 fail to self-renew efficiently post-transplantation.^[18] 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.^[19]

Further reading

• Smith SS, Kaplan BE, Sowers LC, Newman EM . 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 . May 1992 . 1584813 . 49160 . 10.1073/pnas.89.10.4744 . 1992PNAS...89.4744S . free .
• Bestor T, Laudano A, Mattaliano R, Ingram V . 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 . October 1988 . 3210246 . 10.1016/0022-2836(88)90122-2 .
• Smith SS . Biological implications of the mechanism of action of human DNA (cytosine-5)methyltransferase . Progress in Nucleic Acid Research and Molecular Biology . 49 . 65–111 . 1994 . 7863011 . 10.1016/S0079-6603(08)60048-3 . 978-0-12-540049-7 .
• Hijmans EM, Voorhoeve PM, Beijersbergen RL, van 't Veer LJ, Bernards R . E2F-5, a new E2F family member that interacts with p130 in vivo . Molecular and Cellular Biology . 15 . 6 . 3082–9 . June 1995 . 7760804 . 230539 . 10.1128/mcb.15.6.3082 .
• Yoder JA, Yen RW, Vertino PM, Bestor TH, Baylin SB . New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase . The Journal of Biological Chemistry . 271 . 49 . 31092–7 . December 1996 . 8940105 . 10.1074/jbc.271.49.31092 . free .
• Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF . Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1 . Science . 277 . 5334 . 1996–2000 . September 1997 . 9302295 . 10.1126/science.277.5334.1996 .
• Kho MR, Baker DJ, Laayoun A, Smith SS . 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 . January 1998 . 9451440 . 10.1006/jmbi.1997.1430 .
• Baylin SB . Tying it all together: epigenetics, genetics, cell cycle, and cancer . Science . 277 . 5334 . 1948–9 . September 1997 . 9333948 . 10.1126/science.277.5334.1948 . 40894549 .
• 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 .
• Michaelson JS, Bader D, Kuo F, Kozak C, Leder P . Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development . Genes & Development . 13 . 15 . 1918–23 . August 1999 . 10444590 . 316925 . 10.1101/gad.13.15.1918 .
• Hsu DW, Lin MJ, Lee TL, Wen SC, Chen X, Shen CK . 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 . August 1999 . 10449766 . 22282 . 10.1073/pnas.96.17.9751 . 1999PNAS...96.9751H . free .
• Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T . DNA methyltransferase Dnmt1 associates with histone deacetylase activity . Nature Genetics . 24 . 1 . 88–91 . January 2000 . 10615135 . 10.1038/71750 . 20428600 .
• Bonfils C, Beaulieu N, Chan E, Cotton-Montpetit J, MacLeod AR . Characterization of the human DNA methyltransferase splice variant Dnmt1b . The Journal of Biological Chemistry . 275 . 15 . 10754–60 . April 2000 . 10753866 . 10.1074/jbc.275.15.10754 . free .
• Rountree MR, Bachman KE, Baylin SB . DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci . Nature Genetics . 25 . 3 . 269–77 . July 2000 . 10888872 . 10.1038/77023 . 26149386 .
• Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP . DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters . Nature Genetics . 25 . 3 . 338–42 . July 2000 . 10888886 . 10.1038/77124 . 10983932 .
• Tatematsu KI, Yamazaki T, Ishikawa F . 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 . August 2000 . 10947852 . 10.1046/j.1365-2443.2000.00359.x . 25185979 . free .
• Mizuno S, Chijiwa T, Okamura T, Akashi K, Fukumaki Y, Niho Y, Sasaki H . Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia . Blood . 97 . 5 . 1172–9 . March 2001 . 11222358 . 10.1182/blood.V97.5.1172 . free .
• Fatemi M, Hermann A, Pradhan S, Jeltsch A . 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 . June 2001 . 11399088 . 10.1006/jmbi.2001.4709 .
• Dintilhac A, Bernués J . HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences . The Journal of Biological Chemistry . 277 . 9 . 7021–8 . March 2002 . 11748221 . 10.1074/jbc.M108417200 . free . 10261/112516 . free .
• 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 . Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor . Science . 295 . 5557 . 1079–82 . February 2002 . 11834837 . 10.1126/science.1065173 . 2002Sci...295.1079D . 11576/2506625 . 29532358 .
• Pradhan S, Kim GD . The retinoblastoma gene product interacts with maintenance human DNA (cytosine-5) methyltransferase and modulates its activity . The EMBO Journal . 21 . 4 . 779–88 . February 2002 . 11847125 . 125847 . 10.1093/emboj/21.4.779 .
• 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 .
• Jair KW, Bachman KE, Suzuki H, Ting AH, Rhee I, Yen RW, Baylin SB, Schuebel KE . De novo CpG island methylation in human cancer cells . Cancer Research . 66 . 2 . 682–92 . January 2006 . 16423997 . 10.1158/0008-5472.CAN-05-1980 .
• Ting AH, Jair KW, Schuebel KE, Baylin SB . Differential requirement for DNA methyltransferase 1 in maintaining human cancer cell gene promoter hypermethylation . Cancer Research . 66 . 2 . 729–35 . January 2006 . 16424002 . 10.1158/0008-5472.CAN-05-1537 .
• Bestor T, Laudano A, Mattaliano R, Ingram V . 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 . October 1988 . 3210246 . 10.1016/0022-2836(88)90122-2 .

External links

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

Notes and References

1. Yen RW, Vertino PM, Nelkin BD, Yu JJ, el-Deiry W, Cumaraswamy A, Lennon GG, Trask BJ, Celano P, Baylin SB . Isolation and characterization of the cDNA encoding human DNA methyltransferase . Nucleic Acids Research . 20 . 9 . 2287–91 . May 1992 . 1594447 . 312343 . 10.1093/nar/20.9.2287 .
2. Hermann A, Goyal R, Jeltsch A . 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 . November 2004 . 15339928 . 10.1074/jbc.M403427200 . free .
3. Yarychkivska O, Shahabuddin Z, Comfort N, Boulard M, Bestor TH . BAH domains and a histone-like motif in DNA methyltransferase 1 (DNMT1) regulate de novo and maintenance methylation in vivo . The Journal of Biological Chemistry . 293 . 50 . 19466–19475 . December 2018 . 30341171. 10.1074/jbc.RA118.004612 . 6302165 . free .
4. Haggerty C, Kretzmer H, Riemenschneider C, et al. . Dnmt1 has de novo activity targeted to transposable elements. . Nature Structural and Molecular Biology . June 2021 . 28 . 7 . 594–603 . 34140676. 10.1038/s41594-021-00603-8 . 8279952 . free .
5. 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 . Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss . Nature Genetics . 43 . 6 . 595–600 . June 2011 . 21532572 . 3102765 . 10.1038/ng.830 .
6. Web site: Entrez Gene: DNMT1 DNA (cytosine-5-)-methyltransferase 1.
7. 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 .
8. 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 . free . 2003CBio...13.1192L .
9. Rountree MR, Bachman KE, Baylin SB . DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci . Nature Genetics . 25 . 3 . 269–77 . July 2000 . 10888872 . 10.1038/77023 . 26149386 .
10. Iida T, Suetake I, Tajima S, Morioka H, Ohta S, Obuse C, Tsurimoto T . PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA . Genes to Cells . 7 . 10 . 997–1007 . October 2002 . 12354094 . 10.1046/j.1365-2443.2002.00584.x . 25310911 . free .
11. Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF . Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1 . Science . 277 . 5334 . 1996–2000 . September 1997 . 9302295 . 10.1126/science.277.5334.1996 .
12. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP . DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters . Nature Genetics . 25 . 3 . 338–42 . July 2000 . 10888886 . 10.1038/77124 . 10983932 .
13. Estève PO, Chin HG, Smallwood A, Feehery GR, Gangisetty O, Karpf AR, Carey MF, Pradhan S . Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication . Genes & Development . 20 . 22 . 3089–103 . November 2006 . 17085482 . 1635145 . 10.1101/gad.1463706 .
14. Robertson KD, Keyomarsi K, Gonzales FA, Velicescu M, Jones PA . 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 . May 2000 . 10773079 . 105379 . 10.1093/nar/28.10.2108.
15. Jones PA, Liang G . Rethinking how DNA methylation patterns are maintained . Nature Reviews. Genetics . 10 . 11 . 805–11 . November 2009 . 19789556 . 2848124 . 10.1038/nrg2651 .
16. Li E, Bestor TH, Jaenisch R . Targeted mutation of the DNA methyltransferase gene results in embryonic lethality . Cell . 69 . 6 . 915–26 . June 1992 . 1606615 . 10.1016/0092-8674(92)90611-F . 19879601 .
17. Hirasawa R, Chiba H, Kaneda M, Tajima S, Li E, Jaenisch R, Sasaki H . Maternal and zygotic Dnmt1 are necessary and sufficient for the maintenance of DNA methylation imprints during preimplantation development . Genes & Development . 22 . 12 . 1607–16 . June 2008 . 18559477 . 2428059 . 10.1101/gad.1667008 .
18. Trowbridge JJ, Snow JW, Kim J, Orkin SH . DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells . Cell Stem Cell . 5 . 4 . 442–9 . October 2009 . 19796624 . 2767228 . 10.1016/j.stem.2009.08.016 .
19. Avgustinova A, Benitah SA . Epigenetic control of adult stem cell function . Nature Reviews. Molecular Cell Biology . 17 . 10 . 643–58 . October 2016 . 27405257 . 10.1038/nrm.2016.76 . 24795361 .