Disease relevance of DNMT3A

• On the other hand, over 74% of cases showed decreased expression of DNMT3A and 3B in leiomyomas compared to the adjacent myometria [1].
• Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis [2].
• These proteins include CCND2 and DNMT3A and may be useful as molecular pathological markers of seminoma [3].
• Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA [4].
• Comparison of human embryonal carcinoma cell lines with breast/ovarian cancer cell lines indicates that DNMT3A2 expression correlates with high de novo methylation activity [5].

High impact information on DNMT3A

• Here we demonstrate that two recently identified DNA methyltransferases, Dnmt3a and Dnmt3b, are essential for de novo methylation and for mouse development [6].
• Although enzymes have been identified that can methylate DNA de novo (Dnmt3a and Dnmt3b) (14), it is unknown how specific patterns of methylation are established in the genome [7].
• Inactivation of both Dnmt3a and Dnmt3b, DNA methyltransferases essential for the initiation of de novo DNA methylation, abolished the establishment of DNA methylation and the silencing of Rhox cluster genes in the embryo proper [8].
• Further, LANA associated with repressed cellular promoters, recruited Dnmt3a to DNA, and facilitated de novo promoter methylation of a down-regulated gene, cadherin 13 (H-cadherin) [4].
• LANA preferentially relocalized Dnmt3a from the nuclear matrix into the chromatin fraction [4].

Chemical compound and disease context of DNMT3A

• To elucidate the underlying mechanism of transcriptional repression, Dnmt3a was purified from mouse lymphosarcoma cells (P1798) by extensive fractionation on five different chromatographic matrices followed by glycerol density gradient centrifugation [9].

Biological context of DNMT3A

• PURPOSE: Three genes, namely DNA methyltransferase (DNMT) 1, DNMT3A, and DNMT3B, coding for DNMTs that affect promoter methylation status are thought to play an important role in the development of cancers [10].
• The DNMT3A and DNMT3B show high homology in the carboxy terminal catalytic domain and contain a conserved cysteine-rich region, which shares homology with the X-linked ATRX gene of the SNF2/SWI family [11].
• We have mapped human DNMT3A and DNMT3B to chromosomes 2p23 and 20q11.2 respectively, and determined the DNMT3B genomic structure [11].
• In fetal testis DNMT1 and DNMT3A expression peaked in mitotically arrested spermatogonia around 21 weeks gestation [12].
• In fetal ovary transcriptional upregulation of DNMT1 and DNMT3A occurred during a very brief period at 16 weeks gestation, when the oocytes proceeded through meiotic prophase [12].

Anatomical context of DNMT3A

• We further show that DNMT3A expression is ubiquitous and can be readily detected in most adult tissues, whereas DNMT3B is expressed at very low levels in most tissues except testis, thyroid and bone marrow [11].
• Significantly, both DNMT3A and DNMT3B expression is elevated in several tumor cell lines to levels comparable to DNMT1 [11].
• Reverse Northern blot analyses demonstrated sex-specific differences in mRNA expression for the maintenance DNMT1 and the de novo DNMT3A in developing testis and ovary [12].
• Fetal gonads showed several fold higher DNMT3A expression levels than fetal brain and adult tissues [12].
• Immunofluorescence experiments localized DNMT3A to discrete nucleolar foci in B spermatogonia and resting fibroblasts [13].

Associations of DNMT3A with chemical compounds

• The importance of these Sp1-binding sites was demonstrated by using a GC-rich DNA-binding protein inhibitor, mithramycin A, i.e. on the basis of decrease in the promoter activities and mRNA expression levels of DNMT3A and DNMT3B [14].
• Biochemical analysis revealed that whereas DNMT3L on its own does not significantly bind to the methyl group donor, S-adenosyl-L-methionine (SAM), it strongly increases the binding of SAM to DNMT3A2 [15].
• Binding of DNMT3L to DNMT3A2 promotes a dramatic reorganization of DNMT3A2 subunits and leads to the formation of specific complexes with enhanced DNA methyltransferase activity and increased SAM binding [15].
• Repair brings its own problems, since it will require remethylation of the replacement cytosine, presumably coupling repair to methylation by either the maintenance methylase Dnmt1 or a de novo enzyme such as Dnmt3a [16].
• Analysis of the sites methylated in vivo using the bisulfite genomic sequencing method confirms the previous finding that some regions of the plasmid are much more methylated by Dnmt3a than other regions on the same plasmid [17].

Regulatory relationships of DNMT3A

• DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction [18].
• The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a [19].
• Finally, the activity of Dnmt3a in vivo was demonstrated when this enzyme was overexpressed in a breast cell line in which Dnmt3a repressed p21 upregulation following DNA damage [20].

Other interactions of DNMT3A

• Recently, two new mammalian DNA methyltransferase genes have been identified, which are referred to as DNMT3A and DNMT3B [21].
• Immunofluorescence analysis and biochemical fractionation showed that all three DNMTs (DNMT1, DNMT3A, and DNMT3B) are associated with the inactive rDNA in the nucleolus [22].
• Previous studies have shown that DNMT3L physically associates with the active de novo DNA methyltransferases, DNMT3A and DNMT3B, and stimulates their catalytic activities in a cell culture system [15].
• Here, we show that Dnmt3L, like Dnmt3a and Dnmt3b, interacts both in vitro and in vivo with the histone deacetylase HDAC1 [23].
• The interaction of SETDB1 with DNMT3A was further characterized and confirmed by in vivo and in vitro interaction studies [24].

Analytical, diagnostic and therapeutic context of DNMT3A

• Analysis of DNA methyltransferase complexes in solution using size exclusion chromatography revealed that DNMT3A2 forms large structures of heterogeneous sizes, whereas DNMT3L appears as a monomer [15].
• Western blots revealed that DNMT3A protein (with catalytic domain) is present at low levels in several tissues and at increased levels in testicular cells and growth-arrested fibroblasts [13].

References