DNMT1

DNMT1
PDBに登録されている構造
PDB	オルソログ検索: RCSB PDBe PDBj
PDBのIDコード一覧
	4YOC, 3EPZ, 3PTA, 3SWR, 4WXX
識別子
記号	DNMT1, ADCADN, AIM, CXXC9, DNMT, HSN1E, MCMT, m.HsaI, DNA (cytosine-5-)-methyltransferase 1, DNA methyltransferase 1
外部ID	OMIM: 126375 MGI: 94912 HomoloGene: 124071 GeneCards: DNMT1
遺伝子の位置 (ヒト)
染色体	19番染色体 (ヒト)
終点	10,231,286 bp
遺伝子の位置 (マウス)
染色体	9番染色体 (マウス)
終点	20,871,184 bp
RNA発現パターン
	さらなる参照発現データ
遺伝子オントロジー
分子機能	• メチルトランスフェラーゼ活性; • DNA結合; • トランスフェラーゼ活性; • promoter-specific chromatin binding; • methyl-CpG binding; • zinc ion binding; • DNA-methyltransferase activity; • クロマチン結合; • 金属イオン結合; • 血漿タンパク結合; • RNA結合; • DNA (cytosine-5-)-methyltransferase activity; • DNA-binding transcription factor activity, RNA polymerase II-specific;
細胞の構成要素	• pericentric heterochromatin; • replication fork; • 核質; • ヘテロクロマチン; • 細胞核;
生物学的プロセス	• C-5 methylation of cytosine; • regulation of transcription, DNA-templated; • maintenance of DNA methylation; • positive regulation of DNA methylation-dependent heterochromatin assembly; • negative regulation of transcription by RNA polymerase II; • transcription, DNA-templated; • メチル化; • DNAメチル化; • positive regulation of gene expression; • negative regulation of gene expression, epigenetic; • positive regulation of histone H3-K4 methylation; • regulation of cell population proliferation; • negative regulation of histone H3-K9 methylation; • cellular response to amino acid stimulus; • 遺伝子発現調節; • Ras protein signal transduction; • negative regulation of transcription, DNA-templated; • DNA methylation on cytosine; • DNA methylation involved in embryo development; • chromatin organization; • DNA methylation on cytosine within a CG sequence; • 遺伝子発現の負の調節; • positive regulation of vascular associated smooth muscle cell proliferation; • negative regulation of vascular associated smooth muscle cell apoptotic process; • negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching;
	出典:Amigo / QuickGO
オルソログ
	1786
	13433
	ENSG00000130816
	ENSMUSG00000004099
	P26358
	P13864
	NM_001130823; NM_001379; NM_001318730; NM_001318731
	NM_001199431; NM_001199432; NM_001199433; NM_010066; NM_001314011
	NP_001124295; NP_001305659; NP_001305660; NP_001370
NP_001186360; NP_001186361; NP_001186362; NP_001300940; NP_034196;
	NP_001391614
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

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（英語版）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^[5]。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^[6]。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^[7]^[8]。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^[9]^[10]。

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^[18]。PCNAやUHRF1（英語版）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^[19]。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^[17]。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^[20]。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^[21]。

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^[22]。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^[23]。

出典

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000130816 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000004099 - Ensembl, May 2017
^ Human PubMed Reference:
^ Mouse PubMed Reference:
^ “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. PMC 312343. PMID 1594447.
^ “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。
^ ^a ^b ^c “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.
^ ^a ^b “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.
^ “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.
^ “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.
^ “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.
^ “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.
^ ^a ^b “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.

外部リンク

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

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000130816 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000004099 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

[pmid1594447-5] “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. PMC 312343. PMID 1594447.

[:1-6] “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.

[:2-7] “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.

[:3-8] “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.

[pmid21532572-9] “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.

[:4-10] “Entrez Gene: DNMT1 DNA (cytosine-5-)-methyltransferase 1”. 2021年8月7日閲覧。

[pmid10888872-11] “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.

[pmid12145218-12] “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.

[pmid12867029-13] “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.

[pmid12354094-14] “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.

[pmid9302295-15] “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.

[pmid10888886-16] “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.

[:0-17] “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.

[:5-18] “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.

[:6-19] “Rethinking how DNA methylation patterns are maintained”. Nature Reviews. Genetics 10 (11): 805–11. (November 2009). doi:10.1038/nrg2651. PMC 2848124. PMID 19789556.

[:7-20] “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.

[:8-21] “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.

[:9-22] “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.

[:10-23] “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.

[1]

DNMT1

機能

相互作用

モデル生物

臨床的意義

出典

関連文献

関連項目

外部リンク