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
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDNMT1, ADCADN, AIM, CXXC9, DNMT, HSN1E, MCMT, m.HsaI, DNA (cytosine-5-)-methyltransferase 1, DNA methyltransferase 1
External IDsOMIM: 126375 MGI: 94912 HomoloGene: 124071 GeneCards: DNMT1
Orthologs
SpeciesHumanMouse
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

Location (UCSC)Chr 19: 10.13 – 10.23 MbChr 9: 20.82 – 20.87 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[6] However, DNMT1 can catalyze de novo DNA methylation in specific genomic contexts, including transposable elements and paternal imprint control regions.[7][8] Aberrant methylation patterns are associated with certain human tumors and developmental abnormalities.[9][10]

See also

Interactions

DNMT1 has been shown to interact with UHRF1,:

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.[18] Its interaction with PCNA and UHRF1 has been implicated in localizing it to the replication fork.[19] The direct co-operation between DNMT1 and G9a coordinates DNA and H3K9 methylation during cell division.[17] 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.[20] It has also been shown that a lack of both maternal and zygotic Dnmt1 results in complete demethylation of imprinted genes in blastocysts.[21]

Clinical significance

DNMT1 plays a critical role in Hematopoietic stem cell (HSC) maintenance. HSCs with reduced DNMT1 fail to self-renew efficiently post-transplantation.[22] 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.[23]

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. Yarychkivska O, Shahabuddin Z, Comfort N, Boulard M, Bestor TH (December 2018). "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. doi:10.1074/jbc.RA118.004612. PMC 6302165. PMID 30341171.
  8. Haggerty C, Kretzmer H, Riemenschneider C, et al. (June 2021). "Dnmt1 has de novo activity targeted to transposable elements". Nature Structural and Molecular Biology. 28 (7): 594–603. doi:10.1038/s41594-021-00603-8. PMC 8279952. PMID 34140676.
  9. 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.
  10. "Entrez Gene: DNMT1 DNA (cytosine-5-)-methyltransferase 1".
  11. 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. S2CID 26149386.
  12. 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.
  13. 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.
  14. 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. S2CID 25310911.
  15. 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.
  16. 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. S2CID 10983932.
  17. 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.
  18. 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.
  19. 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.
  20. 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. S2CID 19879601.
  21. 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.
  22. 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.
  23. 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. S2CID 24795361.

Further reading
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