“DNMT1”的意思、由来-开放百科全书

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 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.^[2] Aberrant methylation patterns are associated with certain human tumors and developmental abnormalities.^[3]^[4]

See also

Interactions

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.^[12] Its interaction with PCNA and UHRF1 has been implicated in localizing it to the replication fork.^[13] The direct co-operation between DNMT1 and G9a coordinates DNA and H3K9 methylation during cell division.^[11] 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.^[14] It has also been shown that a lack of both maternal and zygotic Dnmt1 results in complete demethylation of imprinted genes in blastocysts.^[15]

Clinical significance

DNMT1 plays a critical role in Hematopoietic stem cell (HSC) maintenance. HSCs with reduced DNMT1 fail to self-renew efficiently post-transplantation.^[16] 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.^[17]

References

1. ^{{cite journal | vauthors = Yen RW, Vertino PM, Nelkin BD, Yu JJ, el-Deiry W, Cumaraswamy A, Lennon GG, Trask BJ, Celano P, Baylin SB | title = Isolation and characterization of the cDNA encoding human DNA methyltransferase | journal = Nucleic Acids Research | volume = 20 | issue = 9 | pages = 2287–91 | date = May 1992 | pmid = 1594447 | pmc = 312343 | doi = 10.1093/nar/20.9.2287 }}
2. ^{{cite journal | vauthors = Hermann A, Goyal R, Jeltsch A | title = The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites | journal = The Journal of Biological Chemistry | volume = 279 | issue = 46 | pages = 48350–9 | date = November 2004 | pmid = 15339928 | doi = 10.1074/jbc.M403427200 }}
3. ^{{cite journal | vauthors = 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 | title = Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss | journal = Nature Genetics | volume = 43 | issue = 6 | pages = 595–600 | date = June 2011 | pmid = 21532572 | pmc = 3102765 | doi = 10.1038/ng.830 }}
4. ^{{cite web | title = Entrez Gene: DNMT1 DNA (cytosine-5-)-methyltransferase 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1786 }}
5. ^¹{{cite journal | vauthors = Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S | title = Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases | journal = The EMBO Journal | volume = 21 | issue = 15 | pages = 4183–95 | date = August 2002 | pmid = 12145218 | pmc = 126147 | doi = 10.1093/emboj/cdf401 }}
6. ^{{cite journal | vauthors = Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH | title = Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin | journal = Current Biology | volume = 13 | issue = 14 | pages = 1192–200 | date = July 2003 | pmid = 12867029 | doi = 10.1016/s0960-9822(03)00432-9 }}
7. ^¹²{{cite journal | vauthors = Rountree MR, Bachman KE, Baylin SB | title = DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci | journal = Nature Genetics | volume = 25 | issue = 3 | pages = 269–77 | date = July 2000 | pmid = 10888872 | doi = 10.1038/77023 }}
8. ^{{cite journal | vauthors = Iida T, Suetake I, Tajima S, Morioka H, Ohta S, Obuse C, Tsurimoto T | title = PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA | journal = Genes to Cells | volume = 7 | issue = 10 | pages = 997–1007 | date = October 2002 | pmid = 12354094 | doi = 10.1046/j.1365-2443.2002.00584.x }}
9. ^{{cite journal | vauthors = Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF | title = Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1 | journal = Science | volume = 277 | issue = 5334 | pages = 1996–2000 | date = September 1997 | pmid = 9302295 | doi = 10.1126/science.277.5334.1996 }}
10. ^{{cite journal | vauthors = Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP | title = DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters | journal = Nature Genetics | volume = 25 | issue = 3 | pages = 338–42 | date = July 2000 | pmid = 10888886 | doi = 10.1038/77124 }}
11. ^¹{{cite journal | vauthors = Estève PO, Chin HG, Smallwood A, Feehery GR, Gangisetty O, Karpf AR, Carey MF, Pradhan S | title = Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication | journal = Genes & Development | volume = 20 | issue = 22 | pages = 3089–103 | date = November 2006 | pmid = 17085482 | pmc = 1635145 | doi = 10.1101/gad.1463706 }}
12. ^{{cite journal | vauthors = Robertson KD, Keyomarsi K, Gonzales FA, Velicescu M, Jones PA | title = 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 | journal = Nucleic Acids Research | volume = 28 | issue = 10 | pages = 2108–13 | date = May 2000 | pmid = 10773079 | pmc = 105379 | doi=10.1093/nar/28.10.2108}}
13. ^{{cite journal | vauthors = Jones PA, Liang G | title = Rethinking how DNA methylation patterns are maintained | journal = Nature Reviews. Genetics | volume = 10 | issue = 11 | pages = 805–11 | date = November 2009 | pmid = 19789556 | pmc = 2848124 | doi = 10.1038/nrg2651 }}
14. ^{{cite journal | vauthors = Li E, Bestor TH, Jaenisch R | title = Targeted mutation of the DNA methyltransferase gene results in embryonic lethality | journal = Cell | volume = 69 | issue = 6 | pages = 915–26 | date = June 1992 | pmid = 1606615 | doi = 10.1016/0092-8674(92)90611-F }}
15. ^{{cite journal | vauthors = Hirasawa R, Chiba H, Kaneda M, Tajima S, Li E, Jaenisch R, Sasaki H | title = Maternal and zygotic Dnmt1 are necessary and sufficient for the maintenance of DNA methylation imprints during preimplantation development | journal = Genes & Development | volume = 22 | issue = 12 | pages = 1607–16 | date = June 2008 | pmid = 18559477 | pmc = 2428059 | doi = 10.1101/gad.1667008 }}
16. ^{{cite journal | vauthors = Trowbridge JJ, Snow JW, Kim J, Orkin SH | title = DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells | journal = Cell Stem Cell | volume = 5 | issue = 4 | pages = 442–9 | date = October 2009 | pmid = 19796624 | pmc = 2767228 | doi = 10.1016/j.stem.2009.08.016 }}
17. ^{{cite journal | vauthors = Avgustinova A, Benitah SA | title = Epigenetic control of adult stem cell function | journal = Nature Reviews. Molecular Cell Biology | volume = 17 | issue = 10 | pages = 643–58 | date = October 2016 | pmid = 27405257 | doi = 10.1038/nrm.2016.76 }}