DNMT1
DNMT1（DNA (cytosine-5)-methyltransferase 1）は、DNAメチル化の過程において、DNAの特定のCpG構造へメチル基の転移を触媒する酵素である。ヒトでは、DNMT1遺伝子によってコードされる。DNMT1はDNAメチルトランスフェラーゼファミリーの一部を構成する。このファミリーには他にDNMT3AやDNMT3Bが含まれる。
機能
この酵素はDNAの維持メチル化を担い、受け継がれたエピジェネティックなパターンの複製の正確性を保証している。ヘミメチル化DNA上のCpGのメチル化に対して非常に明確な選択性を有する。しかしながら、DNMT1はトランスポゾンや父親由来のインプリンティング制御領域など特定のゲノム条件下ではde novoメチル化も触媒する。メチル化パターンの異常は、ヒトの特定種の腫瘍や発生異常と関係している。
相互作用
DNMT1は次に挙げる因子と相互作用することが示されている。
DNMT1は細胞周期のS期に高度に転写され、娘DNA鎖に新たに形成されたヘミメチル化部位のメチル化に必要である。PCNAやUHRF1との相互作用は、DNMT1の複製フォークへの局在への関与が示唆されている。DNMT1とG9aの直接的な協働は、細胞分裂時のDNAとヒストンH3リジン9番残基（H3K9）のメチル化を調整している。このクロマチンのメチル化は、哺乳類の発生過程での遺伝子発現の安定的な抑制に必要である。
モデル生物
遺伝子ノックアウト実験からは、この酵素がマウス細胞におけるメチル化の大部分を担っていることが示されており、胚発生にも必要不可欠である。母性因子と接合子由来のDnmt1の双方の欠損によって、胚盤胞ではインプリンティング領域が完全に脱メチル化されることも示されている。
臨床的意義
DNMT1は造血幹細胞（HSC）において重要な役割を果たす。DNMT1が減少したHSCは、移植後に効率的に自己複製を行うことができない。腸管上皮幹細胞（ISC）や乳腺幹細胞（MaSC）など他の種類の幹細胞でも重要であることが示されている。DNMT1の条件的欠失は、腸管のメチル化の全体的な低下と腸陰窩の拡大を引き起こし、ISCの分化のタイミングやMaSCの増殖と維持に変化が生じる。
出典
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000130816 - Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000004099 - Ensembl, May 2017
- ↑ Human PubMed Reference:
- ↑ Mouse PubMed Reference:
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- ↑ “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.
- ↑ “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.
- ↑ “Dnmt1 has de novo activity targeted to transposable elements.”. Nature Structural and Molecular Biology. (June 2021). doi:10.1038/s41594-021-00603-8. PMID 34140676.
- ↑ “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. PMC 3102765. PMID 21532572.
- ↑ “Entrez Gene: DNMT1 DNA (cytosine-5-)-methyltransferase 1”. 2021年8月7日閲覧。
- 1 2 3 “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.
- 1 2 “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. PMC 126147. PMID 12145218.
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- ↑ “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.
- 1 2 “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. PMC 1635145. PMID 17085482.
- ↑ “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. PMC 105379. PMID 10773079.
- ↑ “Rethinking how DNA methylation patterns are maintained”. Nature Reviews. Genetics 10 (11): 805–11. (November 2009). doi:10.1038/nrg2651. PMC 2848124. PMID 19789556.
- ↑ “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.
- ↑ “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. PMC 2428059. PMID 18559477.
- ↑ “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. PMC 2767228. PMID 19796624.
- ↑ “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.
関連文献
- “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). doi:10.1073/pnas.89.10.4744. PMC 49160. PMID 1584813.
- “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). doi:10.1016/0022-2836(88)90122-2. PMID 3210246.
- “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). doi:10.1016/S0079-6603(08)60048-3. ISBN 9780125400497. PMID 7863011.
- “E2F-5, a new E2F family member that interacts with p130 in vivo”. Molecular and Cellular Biology 15 (6): 3082–9. (June 1995). doi:10.1128/mcb.15.6.3082. PMC 230539. PMID 7760804.
- “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). doi:10.1074/jbc.271.49.31092. PMID 8940105.
- “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.
- “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). doi:10.1006/jmbi.1997.1430. PMID 9451440.
- “Tying it all together: epigenetics, genetics, cell cycle, and cancer”. Science 277 (5334): 1948–9. (September 1997). doi:10.1126/science.277.5334.1948. PMID 9333948.
- “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). doi:10.1093/nar/27.11.2291. PMC 148793. PMID 10325416.
- “Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development”. Genes & Development 13 (15): 1918–23. (August 1999). doi:10.1101/gad.13.15.1918. PMC 316925. PMID 10444590.
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- “DNA methyltransferase Dnmt1 associates with histone deacetylase activity”. Nature Genetics 24 (1): 88–91. (January 2000). doi:10.1038/71750. PMID 10615135.
- “Characterization of the human DNA methyltransferase splice variant Dnmt1b”. The Journal of Biological Chemistry 275 (15): 10754–60. (April 2000). doi:10.1074/jbc.275.15.10754. PMID 10753866.
- “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.
- “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.
- “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). doi:10.1046/j.1365-2443.2000.00359.x. PMID 10947852.
- “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). doi:10.1182/blood.V97.5.1172. PMID 11222358.
- “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). doi:10.1006/jmbi.2001.4709. PMID 11399088.
- “HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences”. The Journal of Biological Chemistry 277 (9): 7021–8. (March 2002). doi:10.1074/jbc.M108417200. PMID 11748221.
- “Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor”. Science 295 (5557): 1079–82. (February 2002). doi:10.1126/science.1065173. PMID 11834837.
- “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). doi:10.1093/emboj/21.4.779. PMC 125847. PMID 11847125.
- “DNMT1 and DNMT3b cooperate to silence genes in human cancer cells”. Nature 416 (6880): 552–6. (April 2002). doi:10.1038/416552a. PMID 11932749.
- “De novo CpG island methylation in human cancer cells”. Cancer Research 66 (2): 682–92. (January 2006). doi:10.1158/0008-5472.CAN-05-1980. PMID 16423997.
- “Differential requirement for DNA methyltransferase 1 in maintaining human cancer cell gene promoter hypermethylation”. Cancer Research 66 (2): 729–35. (January 2006). doi:10.1158/0008-5472.CAN-05-1537. PMID 16424002.
- “Mammalian cytosine DNA methyltransferase Dnmt1: enzymatic mechanism, novel mechanism-based inhibitors, and RNA-directed DNA methylation”. Current Medicinal Chemistry 15 (1): 92–106. (2008). doi:10.2174/092986708783330700. PMID 18220765.
- “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). doi:10.1016/0022-2836(88)90122-2. PMID 3210246.