Biology:DNMT1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[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

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.[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.[13] 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]

References

  1. ↑ "Isolation and characterization of the cDNA encoding human DNA methyltransferase". Nucleic Acids Research 20 (9): 2287–91. May 1992. doi:10.1093/nar/20.9.2287. PMID 1594447. 
  2. ↑ "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. doi:10.1074/jbc.M403427200. PMID 15339928. 
  3. ↑ "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. doi:10.1074/jbc.RA118.004612. PMID 30341171. 
  4. ↑ "Dnmt1 has de novo activity targeted to transposable elements.". Nature Structural and Molecular Biology 28 (7): 594–603. June 2021. doi:10.1038/s41594-021-00603-8. PMID 34140676. 
  5. ↑ "Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss". Nature Genetics 43 (6): 595–600. June 2011. doi:10.1038/ng.830. PMID 21532572. 
  6. ↑ "Entrez Gene: DNMT1 DNA (cytosine-5-)-methyltransferase 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1786. 
  7. ↑ 7.0 7.1 7.2 "DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci". Nature Genetics 25 (3): 269–77. July 2000. doi:10.1038/77023. PMID 10888872. 
  8. ↑ 8.0 8.1 "Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases". The EMBO Journal 21 (15): 4183–95. August 2002. doi:10.1093/emboj/cdf401. PMID 12145218. 
  9. ↑ "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. doi:10.1016/s0960-9822(03)00432-9. PMID 12867029. 
  10. ↑ "PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA". Genes to Cells 7 (10): 997–1007. October 2002. doi:10.1046/j.1365-2443.2002.00584.x. PMID 12354094. 
  11. ↑ "Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1". Science 277 (5334): 1996–2000. September 1997. doi:10.1126/science.277.5334.1996. PMID 9302295. 
  12. ↑ "DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters". Nature Genetics 25 (3): 338–42. July 2000. doi:10.1038/77124. PMID 10888886. 
  13. ↑ 13.0 13.1 "Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication". Genes & Development 20 (22): 3089–103. November 2006. doi:10.1101/gad.1463706. PMID 17085482. 
  14. ↑ "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. doi:10.1093/nar/28.10.2108. PMID 10773079. 
  15. ↑ "Rethinking how DNA methylation patterns are maintained". Nature Reviews. Genetics 10 (11): 805–11. November 2009. doi:10.1038/nrg2651. PMID 19789556. 
  16. ↑ "Targeted mutation of the DNA methyltransferase gene results in embryonic lethality". Cell 69 (6): 915–26. June 1992. doi:10.1016/0092-8674(92)90611-F. PMID 1606615. 
  17. ↑ "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. doi:10.1101/gad.1667008. PMID 18559477. 
  18. ↑ "DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells". Cell Stem Cell 5 (4): 442–9. October 2009. doi:10.1016/j.stem.2009.08.016. PMID 19796624. 
  19. ↑ "Epigenetic control of adult stem cell function". Nature Reviews. Molecular Cell Biology 17 (10): 643–58. October 2016. doi:10.1038/nrm.2016.76. PMID 27405257. 

Further reading

External links




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