DNMT3A

DNA (cytosine-5 -) - methyltransferase 3 alpha
	; Presented based on PDB .
Available Structures
PDB	Ortholog Search: PDBe , RCSB
PDB ID List
	, , , ,
Identifiers
Symbol	; DNMT3A2; M. HsaIIIA; TBRS
External IDs	IUPHAR : ChEMBL : GeneCards :
EC number
Gene ontology
Function	•; •; •; •; •; •; •;
Cell component	•; •; •; •; •; •; •;
Biological process	•; •; •; •; •; •; •; •; •; •; •; •; •;
	Sources: Amigo / QuickGO
RNA expression profile
Orthologists

DNA (cytosine-5) methyltransferase 3A is an enzyme that catalyzes the transfer of methyl groups to CpG methylation sites in DNA ( DNA methylation ). The enzyme is encoded in humans by the DNMT3A gene ^[1] ^[2] .

This protein, along with and , is a member of the family of DNA methyltransferases ^[1] ^[2] .

Content

Function

CpG methylation - epigenetic modifications important for embryonic development, imprinting and inactivation of the X chromosome . Studies in mice have shown that DNA methylation is necessary for the development of mammals. This gene encodes a DNA methyltransferase, which is believed to carry out de novo methylation, rather than serving existing methylation sites. The protein is localized in the cytoplasm and nucleus and its expression is regulated as the body develops. There are alternative splicing options encoding different isoforms ^[3] .

Clinical Importance

A study of this gene in mice showed that a decrease in its expression in aging animals causes a decrease in cognitive long-term memory ^[4] .

The gene also mutates frequently in cancer, being one of the 127 most frequently mutated genes identified in the Atlas of the Cancer Genome project - a work in which the genome was completely sequenced for 3281 different types of cancer ^[5] . In this study, DNMT3a mutations were most often observed in acute myeloid leukemia , where they occurred in more than 25% of cases. These mutations most often occur at the R882 position in the protein and can lead to the loss of protein function ^[6] . Mutations in the DNMT3A gene, regardless of other factors, are associated with an unfavorable prognosis of survival in acute myeloid leukemia ^[7] .

Interactions

Dnmt3a has been found to interact with:

DNMT1 ^[8] ,
DNMT3b ^[9] ^[8] ^[10] ,
HDAC1 ^[11] ,
Myc ^[12] ,
PIAS1 ^[9] ,
PIAS2 ^[9] ,
SUV39H1 ^[13] ,
UBE2I ^[9] and
ZNF238 ^[11] .

Notes

↑ ¹ ² Okano M. , Xie S. , Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. (English) // Nature genetics. - 1998. - Vol. 19, no. 3 . - P. 219-220. - DOI : 10.1038 / 890 . - PMID 9662389 .
↑ ¹ ² Xie S. , Wang Z. , Okano M. , Nogami M. , Li Y. , He WW , Okumura K. , Li E. Cloning, expression and chromosome locations of the human DNMT3 gene family. (English) // Gene. - 1999. - Vol. 236, no. 1 . - P. 87-95. - PMID 10433969 .
↑ Entrez Gene: DNMT3A DNA (cytosine-5 -) - methyltransferase 3 alpha (neopr.) .
↑ Oliveira AM , Hemstedt TJ , Bading H. Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities. (English) // Nature neuroscience. - 2012. - Vol. 15, no. 8 . - P. 1111-1113. - 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. Mutational landscape and significance across 12 major cancer types. (Eng.) // Nature. - 2013 .-- Vol. 502, no. 7471 . - P. 333—339. - DOI : 10.1038 / nature12634 . - PMID 24132290 .
↑ Shih AH , Abdel-Wahab O. , Patel JP , Levine RL The role of mutations in epigenetic regulators in myeloid malignancies. (Eng.) // Nature reviews. Cancer - 2012. - Vol. 12, no. 9 . - P. 599-612. - DOI : 10.1038 / nrc3343 . - PMID 22898539 .
↑ Ley TJ , Ding L. , Walter MJ , McLellan MD , Lamprecht T. , Larson DE , Kandoth C. , Payton JE , Baty J. , Welch J. , Harris CC , Lichti CF , Townsend RR , Fulton RS , Dooling DJ , Koboldt DC , Schmidt H. , Zhang Q. , Osborne JR , Lin L. , O'Laughlin M. , McMichael JF , Delehaunty KD , McGrath SD , Fulton LA , Magrini VJ , Vickery TL , Hundal J. , Cook LL , Conyers JJ , Swift GW , Reed JP , Alldredge PA , Wylie T. , Walker J. , Kalicki J. , Watson MA , Heath S. , Shannon WD , Varghese N. , Nagarajan R. , Westervelt P. , Tomasson MH , Link DC , Graubert TA , DiPersio JF , Mardis ER , Wilson RK DNMT3A mutations in acute myeloid leukemia. (English) // The New England journal of medicine. - 2010 .-- Vol. 363, no. 25 . - P. 2424-2433. - DOI : 10.1056 / NEJMoa1005143 . - PMID 21067377 .
↑ ¹ ² Kim GD , Ni J. , Kelesoglu N. , Roberts RJ , Pradhan S. Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases. (Eng.) // The EMBO journal. - 2002. - Vol. 21, no. 15 . - P. 4183-4195. - PMID 12145218 .
↑ ¹ ² ³ ⁴ Ling Y. , Sankpal UT , Robertson AK , McNally JG , Karpova T. , Robertson KD Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription. (English) // Nucleic acids research. - 2004. - Vol. 32, no. 2 . - P. 598-610. - DOI : 10.1093 / nar / gkh195 . - PMID 14752048 .
↑ Lehnertz B. , Ueda Y. , Derijck AA , Braunschweig U. , Perez-Burgos L. , Kubicek S. , Chen T. , Li E. , Jenuwein T. , Peters AH Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. (English) // Current biology: CB. - 2003. - Vol. 13, no. 14 . - P. 1192-1200. - PMID 12867029 .
↑ ¹ ² Fuks F. , Burgers WA , Godin N. , Kasai M. , Kouzarides T. Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. (Eng.) // The EMBO journal. - 2001. - Vol. 20, no. 10 . - P. 2536-2544. - DOI : 10.1093 / emboj / 20.10.2536 . - 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. Myc represses transcription through recruitment of DNA methyltransferase corepressor. (Eng.) // The EMBO journal. - 2005. - Vol. 24, no. 2 . - P. 336—346. - DOI : 10.1038 / sj.emboj.7600509 . - PMID 15616584 .
↑ Fuks F. , Hurd PJ , Deplus R. , Kouzarides T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. (English) // Nucleic acids research. - 2003. - Vol. 31, no. 9 . - P. 2305-2312. - PMID 12711675 .

[pmid9662389-1] ¹ ² Okano M. , Xie S. , Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. (English) // Nature genetics. - 1998. - Vol. 19, no. 3 . - P. 219-220. - DOI : 10.1038 / 890 . - PMID 9662389 .

[pmid10433969-2] ¹ ² Xie S. , Wang Z. , Okano M. , Nogami M. , Li Y. , He WW , Okumura K. , Li E. Cloning, expression and chromosome locations of the human DNMT3 gene family. (English) // Gene. - 1999. - Vol. 236, no. 1 . - P. 87-95. - PMID 10433969 .

[entrez-3] Entrez Gene: DNMT3A DNA (cytosine-5 -) - methyltransferase 3 alpha (neopr.) .

[pmid22751036-4] Oliveira AM , Hemstedt TJ , Bading H. Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities. (English) // Nature neuroscience. - 2012. - Vol. 15, no. 8 . - P. 1111-1113. - DOI : 10.1038 / nn . 3151 . - PMID 22751036 .

[pmid24132290-5] 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. Mutational landscape and significance across 12 major cancer types. (Eng.) // Nature. - 2013 .-- Vol. 502, no. 7471 . - P. 333—339. - DOI : 10.1038 / nature12634 . - PMID 24132290 .

[6] Shih AH , Abdel-Wahab O. , Patel JP , Levine RL The role of mutations in epigenetic regulators in myeloid malignancies. (Eng.) // Nature reviews. Cancer - 2012. - Vol. 12, no. 9 . - P. 599-612. - DOI : 10.1038 / nrc3343 . - PMID 22898539 .

[7] Ley TJ , Ding L. , Walter MJ , McLellan MD , Lamprecht T. , Larson DE , Kandoth C. , Payton JE , Baty J. , Welch J. , Harris CC , Lichti CF , Townsend RR , Fulton RS , Dooling DJ , Koboldt DC , Schmidt H. , Zhang Q. , Osborne JR , Lin L. , O'Laughlin M. , McMichael JF , Delehaunty KD , McGrath SD , Fulton LA , Magrini VJ , Vickery TL , Hundal J. , Cook LL , Conyers JJ , Swift GW , Reed JP , Alldredge PA , Wylie T. , Walker J. , Kalicki J. , Watson MA , Heath S. , Shannon WD , Varghese N. , Nagarajan R. , Westervelt P. , Tomasson MH , Link DC , Graubert TA , DiPersio JF , Mardis ER , Wilson RK DNMT3A mutations in acute myeloid leukemia. (English) // The New England journal of medicine. - 2010 .-- Vol. 363, no. 25 . - P. 2424-2433. - DOI : 10.1056 / NEJMoa1005143 . - PMID 21067377 .

[pmid12145218-8] ¹ ² Kim GD , Ni J. , Kelesoglu N. , Roberts RJ , Pradhan S. Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases. (Eng.) // The EMBO journal. - 2002. - Vol. 21, no. 15 . - P. 4183-4195. - PMID 12145218 .

[pmid14752048-9] ¹ ² ³ ⁴ Ling Y. , Sankpal UT , Robertson AK , McNally JG , Karpova T. , Robertson KD Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription. (English) // Nucleic acids research. - 2004. - Vol. 32, no. 2 . - P. 598-610. - DOI : 10.1093 / nar / gkh195 . - PMID 14752048 .

[pmid12867029-10] Lehnertz B. , Ueda Y. , Derijck AA , Braunschweig U. , Perez-Burgos L. , Kubicek S. , Chen T. , Li E. , Jenuwein T. , Peters AH Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. (English) // Current biology: CB. - 2003. - Vol. 13, no. 14 . - P. 1192-1200. - PMID 12867029 .

[pmid11350943-11] ¹ ² Fuks F. , Burgers WA , Godin N. , Kasai M. , Kouzarides T. Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. (Eng.) // The EMBO journal. - 2001. - Vol. 20, no. 10 . - P. 2536-2544. - DOI : 10.1093 / emboj / 20.10.2536 . - PMID 11350943 .

[pmid15616584-12] 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. Myc represses transcription through recruitment of DNA methyltransferase corepressor. (Eng.) // The EMBO journal. - 2005. - Vol. 24, no. 2 . - P. 336—346. - DOI : 10.1038 / sj.emboj.7600509 . - PMID 15616584 .

[pmid12711675-13] Fuks F. , Hurd PJ , Deplus R. , Kouzarides T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. (English) // Nucleic acids research. - 2003. - Vol. 31, no. 9 . - P. 2305-2312. - PMID 12711675 .