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DNA methyltransferase

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N-6 DNA Methylase
crystal structure of type i restriction enzyme ecoki m protein (ec 2.1.1.72) (m.ecoki)
Identifiers
SymbolN6_Mtase
PfamPF02384
PfamclanCL0063
InterProIPR003356
PROSITEPDOC00087
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary
HsdM N-terminal domain
Identifiers
SymbolHsdM_N
PfamPF12161
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary
C-5 cytosine-specific DNA methylase
structure of human dnmt2, an enigmatic dna methyltransferase homologue
Identifiers
SymbolDNA_methylase
PfamPF00145
PfamclanCL0063
InterProIPR001525
PROSITEPDOC00089
SCOP21hmy/SCOPe/SUPFAM
CDDcd00315
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary
DNA methylase
crystal structure of methyltransferase mboiia (moraxella bovis)
Identifiers
SymbolN6_N4_Mtase
PfamPF01555
PfamclanCL0063
InterProIPR002941
PROSITEPDOC00088
SCOP21boo/SCOPe/SUPFAM
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary

Inbiochemistry,theDNA methyltransferase(DNA MTase,DNMT) family ofenzymescatalyzethe transfer of amethyl grouptoDNA.DNA methylationserves a wide variety of biological functions. All the known DNA methyltransferases useS-adenosyl methionine(SAM) as the methyl donor.

Classification[edit]

Substrate[edit]

MTases can be divided into three different groups on the basis of the chemical reactions they catalyze:

m6A and m4C methyltransferases are found primarily in prokaryotes (although recent evidence has suggested that m6A is abundant in eukaryotes[1]). m5C methyltransferases are found in some lower eukaryotes, in most higher plants, and in animals beginning with theechinoderms.

The m6A methyltransferases (N-6 adenine-specific DNA methylase) (A-Mtase) areenzymesthat specifically methylate the amino group at the C-6 position ofadeninesin DNA. They are found in the three existing types ofbacterialrestriction-modification systems(in type I system the A-Mtase is theproductof the hsdM gene, and in type III it is theproductof the mod gene). Theseenzymesare responsible for themethylationof specific DNAsequencesin order to prevent the host from digesting its owngenomevia itsrestriction enzymes.These methylases have the samesequencespecificity as their corresponding restriction enzymes. These enzymes contain aconservedmotifAsp/Asn-Pro-Pro-Tyr/Phein their N-terminal section, thisconservedregion could be involved insubstratebindingor in thecatalyticactivity.[2][3][4][5]Thestructureof N6-MTase TaqI (M.TaqI) has been resolved to 2.4A.Themoleculefoldsinto 2 domains, an N-terminal catalytic domain, which contains thecatalyticandcofactorbinding sites, and comprises a central 9-stranded beta-sheet, surrounded by 5 helices; and a C-terminal DNA recognition domain, which is formed by 4 smallbeta-sheetsand 8alpha-helices.The N- and C-terminaldomainsform a cleft that accommodates the DNAsubstrate.[6]A classification of N-MTases has been proposed, based onconservedmotif(CM) arrangements.[5]According to this classification, N6-MTases that have a DPPY motif (CM II) occurring after the FxGxG motif (CM I) are designated D12 class N6-adenine MTases. The type I restriction and modification system is composed of threepolypeptidesR, M and S. The M (hsdM) and Ssubunitstogether form amethyltransferasethatmethylatestwoadenineresiduesincomplementarystrands of a bipartite DNArecognition sequence.In the presence of the R subunit, thecomplexcan also act as anendonuclease,binding to the same targetsequencebut cutting the DNA some distance from this site. Whether the DNA is cut or modified depends on the methylation state of the targetsequence.When the target site is unmodified, the DNA is cut. When the target site is hemimethylated, the complex acts as a maintenance methyltransferase, modifying the DNA so that both strands becomemethylated.hsdM contains analpha-helicaldomainat theN-terminus,the HsdM N-terminal domain.[7]

Among the m6A methyltransferases (N-6 adenine-specific DNA methylase) there is a group of orphan MTases that do not participate in the bacterial restriction/methylation system.[8]These enzymes have a regulatory role in gene expression and cell cycle regulation.EcoDamfromE. coli[9]and CcrM fromCaulobacter crescentus[10]are well characterized members of these family. More recently, CamA fromClostridioides difficile,was shown to play key functional roles insporulation,biofilmformations and host-adaptation.[11]

m4C methyltransferases (N-4 cytosine-specific DNA methylases) areenzymesthat specifically methylate the amino group at the C-4 position ofcytosinesin DNA.[5]Suchenzymesare found as components of type II restriction-modification systems inprokaryotes.Such enzymes recognise a specificsequencein DNA and methylate acytosinein thatsequence.By this action they protect DNA fromcleavageby type II restriction enzymes that recognise the samesequence[citation needed]

m5C methyltransferases (C-5 cytosine-specific DNA methylase) (C5 Mtase) are enzymes that specifically methylate the C-5carbonofcytosinesin DNA to produceC5-methylcytosine.[12][13][14]Inmammaliancells, cytosine-specificmethyltransferasesmethylate certainCpGsequences, which are believed to modulategene expressionandcell differentiation.Inbacteria,theseenzymesare a component of restriction-modification systems and serve as valuable tools for the manipulation of DNA.[13][15]Thestructureof HhaI methyltransferase (M.HhaI) has been resolved to 2.5A:the molecule folds into 2domains- a largercatalyticdomain containing catalytic andcofactorbinding sites, and a smaller DNA recognition domain.[16]

Highly conserved DNA methyltransferases of the m4C, m5C, and m6A types have been reported,[17]which appear as promising targets for the development of novel epigenetic inhibitors to fight bacterial virulence, antibiotic resistance, among other biomedical applications.

De novo vs. maintenance[edit]

De novomethyltransferases recognize something in the DNA that allows them to newly methylate cytosines. These are expressed mainly in early embryo development and they set up the pattern of methylation.De novomethyltransferases are also active when a signal-responsive cell, such as aneuron,needs to alter protein expression.[18]As an example, whenfear conditioningcreates a newmemoryin a rat, 9.17% of the genes in the rathippocampusneuron genome are differentially methylated.[19]

Maintenance methyltransferasesadd methylation to DNA when one strand is already methylated. These work throughout the life of the organism to maintain the methylation pattern that had been established by the de novo methyltransferases.[citation needed]

Mammalian[edit]

At least four differently active DNA methyltransferases have been identified in mammals. They are namedDNMT1,[20]two isoforms transcribed from theDNMT3agene: DNMT3a1 and DNMT3a2,[21]andDNMT3b.[22]Recently, another enzyme DNMT3c has been discovered specifically expressed in the male germline in the mouse.[23]

Some activation signals on anucleosome.Nucleosomesconsist of four pairs ofhistoneproteins in a tightly assembled core region plus up to 30% of each histone remaining in a loosely organized tail (only one tail of each pair is shown). DNA is wrapped around the histone core proteins inchromosomes.The lysines (K) are designated with a number showing their position as, for instance (K4), indicating lysine as the 4th amino acid from the amino (N) end of the tail in the histone protein.Methylations{Me}, andacetylations[Ac] are commonpost-translational modificationson the lysines of the histone tails.

[citation needed]

Some repression signals on anucleosome.

Manzo et al.[24]observed differences in genomic binding of DNMT3a1, DNMT3a2 and DNMT3b. They found 3,970 regions exclusively enriched for DNMT3a1, 3,838 exclusively enriched for DNMT3a2 and 3,432 exclusively enriched for DNMT3b.

The DNMT enzymes are not only regulated in their methylating locations on the genome by where they bind to DNA,[24]but they are also regulated by thepost-translational modificationson thehistoneproteins of thenucleosomesaround which the genomic DNA is wrapped (see Figures). Rose and Klose[25]reviewed the relationship between DNA methylation andhistonelysinemethylation. For example, they indicated that H3K4me3 appears to block DNA methylation while H3K9me3 plays a role in promoting DNA methylation.

DNMT3L[26]is a protein closely related to DNMT3a and DNMT3b in structure and critical for DNA methylation, but appears to be inactive on its own.

DNMT1[edit]

DNMT1is the most abundant DNA methyltransferase in mammalian cells, and considered to be the key maintenance methyltransferase inmammals.It predominantlymethylateshemimethylatedCpGdi-nucleotides in the mammalian genome. The recognition motif for the human enzyme involves only three of the bases in the CpG dinucleotide pair: a C on one strand and CpG on the other. This relaxed substrate specificity requirement allows it to methylate unusual structures like DNA slippage intermediates at de novo rates that equal its maintenance rate.[27]Like other DNA cytosine-5 methyltransferases the human enzyme recognizes flipped out cytosines in double stranded DNA and operates by the nucleophilic attack mechanism.[28]In human cancer cells DNMT1 is responsible for bothde novoand maintenance methylation of tumor suppressor genes.[29][30]Theenzymeis about 1,620amino acidslong. The first 1,100 amino acids constitute the regulatory domain of the enzyme, and the remaining residues constitute the catalytic domain. These are joined byGly-Lysrepeats. Both domains are required for the catalytic function of DNMT1.[citation needed]

DNMT1 has severalisoforms,the somatic DNMT1, a splice variant (DNMT1b) and anoocyte-specific isoform (DNMT1o). DNMT1o is synthesized and stored in thecytoplasmof the oocyte and translocated to thecell nucleusduring earlyembryonicdevelopment, while the somatic DNMT1 is always found in the nucleus ofsomatictissue.[citation needed]

DNMT1 null mutantembryonic stem cellswere viable and contained a small percentage of methylated DNA and methyltransferase activity. Mouse embryos homozygous for a deletion in Dnmt1 die at 10–11 days gestation.[31]

TRDMT1[edit]

Although this enzyme has strong sequence similarities with 5-methylcytosine methyltransferases of both prokaryotes and eukaryotes, in 2006, the enzyme was shown to methylate position 38 inaspartic acidtransfer RNA and does not methylate DNA.[32]The name for this methyltransferase has been changed from DNMT2 to TRDMT1 (tRNA aspartic acid methyltransferase 1) to better reflect its biological function.[33]TRDMT1 is the first RNA cytosine methyltransferase to be identified in human cells.

DNMT3[edit]

DNMT3is a family ofDNAmethyltransferases that could methylate hemimethylated and unmethylatedCpGat the same rate. The architecture of DNMT3 enzymes is similar to that of DNMT1, with a regulatory region attached to a catalytic domain. There are at least five members of the DNMT3 family: DNMT3a1, DNMT3a2, 3b, 3c and 3L.[citation needed]

DNMT3a1, DNMT3a2 and DNMT3b can mediate methylation ofCpG sitesin gene promoters, resulting ingene repression.These DNA methyltransferases can also methylate CpG sites within the coding regions of genes, where such methylation can increase gene transcription.[34]Work with DNMT3a1 showed it preferentially localized to CpG islands bivalently marked by H3K4me3 (a transcription promoting mark) and H3K27me3 (a transcription repressive mark), coinciding with thepromotersof manytranscription factors.Work with DNMT3a2, inneurons,found that the DNA methylation changes caused by DNMT3a2 predominantly occur in intergenic and intronic regions. These intergenic and intronic DNA methylations were thought to likely regulateenhanceractivity,alternative splicingor the expression ofnon-coding RNAs.[35]

DNMT3a1 can co-localize withheterochromatinprotein (HP1) and methyl-CpG-binding protein (MeCBP), among a number of other factors.[36]They can also interact with DNMT1, which might be a co-operative event during DNA methylation. DNMT3a prefersCpGmethylationto CpA, CpT, and CpC methylation, though there appears to be some sequence preference of methylation for DNMT3a and DNMT3b. DNMT3a methylatesCpGsites at a rate much slower than DNMT1, but greater than DNMT3b.

The expression of DNMT3a2 differs from DNMT3a1 and DNMT3b because DNMT3a2 expression occurs in the pattern of animmediate early gene.DNMT3a2 is induced to express in neurons, for instance, by new neuronal activity.[37][35]This may be of importance in establishing long-termmemory.[38]In a rat, high levels of new DNA methylations inneuronsof thehippocampusoccur after a memorable event is imposed on a rat, such as contextualfear conditioning.[19]Bayraktar and Kreutz[39]found that DNMT inhibitors, applied in the brain, prevented long-term memories from forming.

DNMT3L contains DNA methyltransferasemotifsand is required for establishing maternalgenomic imprints,despite beingcatalyticallyinactive. DNMT3L is expressed duringgametogenesiswhengenomic imprintingtakes place. The loss of DNMT3L leads to bi-allelicexpression of genes normally not expressed by the maternal allele. DNMT3L interacts with DNMT3a and DNMT3b and co-localized in the nucleus. Though DNMT3L appears incapable ofmethylation,it may participate intranscriptionalrepression.

Clinical significance[edit]

DNMT inhibitors[edit]

Main article:Hypomethylating agent

Because of theepigenetic effectsof the DNMT family, someDNMT inhibitorsare under investigation for treatment of some cancers:[40]

See also[edit]

References[edit]

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Further reading[edit]

External links[edit]

This article incorporates text from the public domainPfamandInterPro:IPR001525
This article incorporates text from the public domainPfamandInterPro:IPR003356
This article incorporates text from the public domainPfamandInterPro:IPR012327
This article incorporates text from the public domainPfamandInterPro:IPR002941
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