DNMT3A
DNA (cytosine-5)-methyltransferase 3A is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the DNMT3A gene.[1][2]
Function
CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase that is thought to function in de novo methylation, rather than the maintenance of existing methylated sites. The protein localizes to the cytoplasm and nucleus and its expression is developmentally regulated. Alternative splicing results in multiple transcript variants encoding different isoforms.[3]
Clinical relevance
The study of this gene in mice has shown its reduced expression in ageing animals causes cognitive long-term memory decline.[4] It is also frequently mutated in cancer, being one of 127 frequently mutated genes identified in the Cancer Genome Atlas project, in a publication involving whole-genome sequencing on 3,281 cancers of various types.[5] In the Cancer Genome Atlas study, DNMT3A mutations were most commonly seen in acute myeloid leukaemia where they occurred in just over 25% of cases sequenced. Mutations were also relatively common in lung cancers.
Interactions
DNMT3A has been shown to interact with:
Model organisms
Model organisms have been used in the study of DNMT3A function. A conditional knockout mouse line called Dnmt3atm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[12] Male and female animals underwent a standardized phenotypic screen[13] to determine the effects of deletion.[14][15][16][17] Additional screens performed: - In-depth immunological phenotyping[18]
| Characteristic | Phenotype |
|---|---|
| All data available at.[13][18] | |
| Insulin | Normal |
| Homozygous viability at P14 | Normal |
| Homozygous Fertility | Normal |
| Body weight | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Dysmorphology | Normal |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Normal |
| Eye morphology | Normal |
| Clinical chemistry | Normal |
| Haematology 16 Weeks | Normal |
| Peripheral blood leukocytes 16 Weeks | Normal |
| Salmonella infection | Normal |
References
- ↑ Okano M, Xie S, Li E (1998). "Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases". Nat. Genet. 19 (3): 219–20. doi:10.1038/890. PMID 9662389.
- ↑ Xie S, Wang Z, Okano M, Nogami M, Li Y, He WW, Okumura K, Li E (1999). "Cloning, expression and chromosome locations of the human DNMT3 gene family". Gene 236 (1): 87–95. doi:10.1016/S0378-1119(99)00252-8. PMID 10433969.
- ↑ "Entrez Gene: DNMT3A DNA (cytosine-5-)-methyltransferase 3 alpha".
- ↑ Oliveira AM, Hemstedt TJ, Bading H (2012). "Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities". Nat. Neurosci. 15 (8): 1111–3. doi:10.1038/nn.3151. PMID 22751036.
- ↑ Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MD, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L (2013). "Mutational landscape and significance across 12 major cancer types". Nature 502 (7471): 333–9. doi:10.1038/nature12634. PMID 24132290.
- 1 2 Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S (2002). "Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases". EMBO J. 21 (15): 4183–95. doi:10.1093/emboj/cdf401. PMC 126147. PMID 12145218.
- 1 2 3 4 Ling Y, Sankpal UT, Robertson AK, McNally JG, Karpova T, Robertson KD (2004). "Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription". Nucleic Acids Res. 32 (2): 598–610. doi:10.1093/nar/gkh195. PMC 373322. PMID 14752048.
- ↑ Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH (2003). "Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin". Curr. Biol. 13 (14): 1192–200. doi:10.1016/s0960-9822(03)00432-9. PMID 12867029.
- 1 2 Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T (2001). "Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription". EMBO J. 20 (10): 2536–44. doi:10.1093/emboj/20.10.2536. PMC 125250. PMID 11350943.
- ↑ Brenner C, Deplus R, Didelot C, Loriot A, Viré E, De Smet C, Gutierrez A, Danovi D, Bernard D, Boon T, Pelicci PG, Amati B, Kouzarides T, de Launoit Y, Di Croce L, Fuks F (2005). "Myc represses transcription through recruitment of DNA methyltransferase corepressor". EMBO J. 24 (2): 336–46. doi:10.1038/sj.emboj.7600509. PMC 545804. PMID 15616584.
- ↑ Fuks F, Hurd PJ, Deplus R, Kouzarides T (2003). "The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase". Nucleic Acids Res. 31 (9): 2305–12. doi:10.1093/nar/gkg332. PMC 154218. PMID 12711675.
- ↑ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
- 1 2 "International Mouse Phenotyping Consortium".
- ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
- ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- ↑ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
- ↑ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
- 1 2 "Infection and Immunity Immunophenotyping (3i) Consortium".
Further reading
- Adams MD, Kerlavage AR, Fleischmann RD, Fuldner RA, Bult CJ, Lee NH, Kirkness EF, Weinstock KG, Gocayne JD, White O (1995). "Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence" (PDF). Nature 377 (6547 Suppl): 3–174. PMID 7566098.
- Bonaldo MF, Lennon G, Soares MB (1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA (1999). "The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors". Nucleic Acids Res. 27 (11): 2291–8. doi:10.1093/nar/27.11.2291. PMC 148793. PMID 10325416.
- Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T (2001). "Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription". EMBO J. 20 (10): 2536–44. doi:10.1093/emboj/20.10.2536. PMC 125250. PMID 11350943.
- Vaute O, Nicolas E, Vandel L, Trouche D (2002). "Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases". Nucleic Acids Res. 30 (2): 475–81. doi:10.1093/nar/30.2.475. PMC 99834. PMID 11788710.
- Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S, Pelicci PG (2002). "Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor". Science 295 (5557): 1079–82. doi:10.1126/science.1065173. PMID 11834837.
- Hata K, Okano M, Lei H, Li E (2002). "Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice". Development 129 (8): 1983–93. PMID 11934864.
- Chen T, Ueda Y, Xie S, Li E (2002). "A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation". J. Biol. Chem. 277 (41): 38746–54. doi:10.1074/jbc.M205312200. PMID 12138111.
- Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S (2002). "Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases". EMBO J. 21 (15): 4183–95. doi:10.1093/emboj/cdf401. PMC 126147. PMID 12145218.
- Yanagisawa Y, Ito E, Yuasa Y, Maruyama K (2002). "The human DNA methyltransferases DNMT3A and DNMT3B have two types of promoters with different CpG contents". Biochim. Biophys. Acta 1577 (3): 457–65. doi:10.1016/S0167-4781(02)00482-7. PMID 12359337.
- Fatemi M, Hermann A, Gowher H, Jeltsch A (2002). "Dnmt3a and Dnmt1 functionally cooperate during de novo methylation of DNA". Eur. J. Biochem. 269 (20): 4981–4. doi:10.1046/j.1432-1033.2002.03198.x. PMID 12383256.
- Weisenberger DJ, Velicescu M, Preciado-Lopez MA, Gonzales FA, Tsai YC, Liang G, Jones PA (2002). "Identification and characterization of alternatively spliced variants of DNA methyltransferase 3a in mammalian cells". Gene 298 (1): 91–9. doi:10.1016/S0378-1119(02)00976-9. PMID 12406579.
- Chedin F, Lieber MR, Hsieh CL (2002). "The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16916–21. doi:10.1073/pnas.262443999. PMC 139244. PMID 12481029.
- Robert MF, Morin S, Beaulieu N, Gauthier F, Chute IC, Barsalou A, MacLeod AR (2003). "DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells". Nat. Genet. 33 (1): 61–5. doi:10.1038/ng1068. PMID 12496760.
- Fuks F, Hurd PJ, Deplus R, Kouzarides T (2003). "The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase". Nucleic Acids Res. 31 (9): 2305–12. doi:10.1093/nar/gkg332. PMC 154218. PMID 12711675.
- Yakushiji T, Uzawa K, Shibahara T, Noma H, Tanzawa H (2003). "Over-expression of DNA methyltransferases and CDKN2A gene methylation status in squamous cell carcinoma of the oral cavity". Int. J. Oncol. 22 (6): 1201–7. doi:10.3892/ijo.22.6.1201. PMID 12738984.
- Ling Y, Sankpal UT, Robertson AK, McNally JG, Karpova T, Robertson KD (2004). "Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription". Nucleic Acids Res. 32 (2): 598–610. doi:10.1093/nar/gkh195. PMC 373322. PMID 14752048.
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