DNA (cytosine-5)-methyltransferases in mouse cells and tissues. studies with a mechanism-based probe

Yoder, Jeffrey A.; Soman, Neilesh S.; Verdine, Gregory L.; Bestor, Timothy H.

doi:10.1006/jmbi.1997.1125

Cited by 320 publications

(228 citation statements)

References 56 publications

(69 reference statements)

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“…Indeed, this enzyme has a 10 ± 40-fold preference for hemimethylated CpGs over unmethylated CpGs (Pradhan et al, 1997(Pradhan et al, , 1999Yoder et al, 1997b). This portion of DNMT1 also contains a cysteine-rich (CXXC) Zn-binding motif, that resembles motifs found in MBD1 and the human Trithorax proteins (Cross et al, 1997).…”

Section: Dna Methylation and Histone Deacetylation: Partners In Transmentioning

confidence: 99%

DNA methylation, chromatin inheritance, and cancer

et al. 2001

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Section: Dna Methylation and Histone Deacetylation: Partners In Transmentioning

confidence: 99%

DNA methylation, chromatin inheritance, and cancer

et al. 2001

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“…These observations strongly suggest a role for DNA methylation in the protection of eukaryotic genome from viral and parasitic sequences. The de-silencing of transposable elements affects the genome stability and the expression of genes through different mechanisms including the activation of RNAi pathways [8,44].…”

Section: Cpg Dinucleotides Location and Func-tionmentioning

confidence: 99%

Dynamic and reversibility of heterochromatic gene silencing in human disease

et al. 2005

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In eukaryotic organisms cellular fate and tissue specific gene expression are regulated by the activity of proteins known as transcription factors that by interacting with specific DNA sequences direct the activation or repression of target genes. The post genomic era has shown that transcription factors are not the unique key regulators of gene expression. Epigenetic mechanisms such as DNA methylation, post-translational modifications of histone proteins, remodeling of nucleosomes and expression of small regulatory RNAs also contribute to regulation of gene expression, determination of cell and tissue specificity and assurance of inheritance of gene expression levels. The relevant contribution of epigenetic mechanisms to a proper cellular function is highlighted by the effects of their deregulation that cooperate with genetic alterations to the development of various diseases and to the establishment and progression of tumors.

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“…The eukaryotic DNA MTases have been grouped into three families based on (i) distinctive properties of their N-terminal regions and (ii) intriguing differences in DNA substrate preferences. The first eukaryotic DNA MTase, Dnmt1, contains a large N-terminal regulatory region of ~1,000 amino acids and shows a preference for hemimethylated DNA in vitro [4][5][6] . Dnmt2, a relatively small protein, contains only the MTase domain, and its function is still unclear 7 .…”

Section: Introductionmentioning

confidence: 99%

The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds

et al. 2002

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The PWWP domain is a weakly conserved sequence motif found in >60 eukaryotic proteins, including the mammalian DNA methyltransferases Dnmt3a and Dnmt3b. These proteins often contain other chromatin-association domains. A 135-residue PWWP domain from mouse Dnmt3b (amino acids 223-357) has been structurally characterized at 1.8 Å resolution. The N-terminal half of this domain resembles a barrel-like five-stranded structure, whereas the C-terminal half contains a five-helix bundle. The two halves are packed against each other to form a single structural module that exhibits a prominent positive electrostatic potential. The PWWP domain alone binds DNA in vitro, probably through its basic surface. We also show that recombinant Dnmt3b2 protein (a splice variant of Dnmt3b) and two N-terminal deletion mutants (Δ218 and Δ369) have approximately equal methyl transfer activity on unmethylated and hemimethylated CpG-containing oligonucleotides. The Δ218 protein, which includes the PWWP domain, binds DNA more strongly than Δ369, which lacks the PWWP domain.Genomic patterns of cytosine methylation at the C5 position play key roles in the organization and control of mammalian chromatin (reviewed in refs 1-3). Mammalian DNA methyltransferases (MTases) all contain a C-terminal catalytic region that is structurally and functionally homologous to bacterial MTases. The eukaryotic DNA MTases have been grouped into three families based on (i) distinctive properties of their N-terminal regions and (ii) intriguing differences in DNA substrate preferences. The first eukaryotic DNA MTase, Dnmt1, contains a large N-terminal regulatory region of ~1,000 amino acids and shows a preference for hemimethylated DNA in vitro [4][5][6] . Dnmt2, a relatively small protein, contains only the MTase domain, and its function is still unclear 7 . Recombinant Dnmt3 acts on unmethylated and hemimethylated DNA at equal rates in vitro 8,9 .The task of dissecting the functional roles of the N-terminal region of the different MTase families is just beginning. These regions vary widely in size and are probably responsible for the diverse biological functions of eukaryotic DNA MTases. These functions include the © 2002 Nature Publishing Group Correspondence should be addressed to X.C. xcheng@emory.edu. Competing interests statementThe authors declare that they have no competing financial interests. HHS Public Access Dnmt3 contains a PWWP domainThe sequences of Dnmt3 orthologs have been determined from human and mouse. They all contain an N-terminal variable region (~280 amino acids in Dnmt3a and ~220 amino acids in Dnmt3b), followed by three stretches of conserved regions: the PWWP motif, six repeats of a CXXC motif and a set of 10 motifs conserved among DNA MTase catalytic regions (Fig. 1a). The PWWP motif 28 was first identified in a gene family related to the hepatomaderived growth factor (HDGF) 29 and WHSC1 genes (Wolf-Hirschhorn Syndrome Candidate) 30 . The corresponding sequence in Dnmt3 is SWWP (Fig. 1b); only the last two positions of the motif...

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DNA (cytosine-5)-methyltransferases in mouse cells and tissues. studies with a mechanism-based probe

Cited by 320 publications

References 56 publications

DNA methylation, chromatin inheritance, and cancer

DNA methylation, chromatin inheritance, and cancer

Dynamic and reversibility of heterochromatic gene silencing in human disease

The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds

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