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A mammalian protein with specific demethylase activity for mCpG DNA
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This paper provides the first evidence that Dnmt3a and Dnmt3b have de novo methyltransferase activity in human cells. The pattern of methylation generated by these two proteins on the stable episome is nonrandom. This study provides evidence that Dnmt3a and Dnmt3b may have preferred targets that are different from DNMT1. Furthermore, Dnmt3a methylates the same sequence on the episome and in the chromosome.
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Hsieh C-L. In vivo activity of murine de novo methyltransferases, Dnmt3a and Dnmat3b. Mol Cell Biol. 19:1999;8211-8218. This paper provides the first evidence that Dnmt3a and Dnmt3b have de novo methyltransferase activity in human cells. The pattern of methylation generated by these two proteins on the stable episome is nonrandom. This study provides evidence that Dnmt3a and Dnmt3b may have preferred targets that are different from DNMT1. Furthermore, Dnmt3a methylates the same sequence on the episome and in the chromosome.
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Hsieh, C.-L.1
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Dnmt3a functions as a de novo methyltransferase whereas no such activity is detected for Dnmt1 in vivo in a Drosophila system. However, Dnmt1 has a higher methylation activity in vitro in the same system. Expression of Dnmt3a can cause developmental defects in Drosophila.
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Lyko F., Ramsahoye B.H., Kashevsky H., Tudor M., Mastrangelo M-A., Orr-Weaver T.L., Jaenish R. Mammalian (cytosine-5) methyltransferases cause genomic DNA methylation and lethality in Drosophila. Nat Genet. 23:1999;363-366. Dnmt3a functions as a de novo methyltransferase whereas no such activity is detected for Dnmt1 in vivo in a Drosophila system. However, Dnmt1 has a higher methylation activity in vitro in the same system. Expression of Dnmt3a can cause developmental defects in Drosophila.
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Lyko, F.1
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DNA methylationtransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development
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Inactivation of Dnmt3a and Dnmt3b in ES cells results in hypomethylation of the satellite sequences, IAP repeats and C-type retroviral DNA. Although disruption of Dnmt3a and Dnmt3b does not influence methylation within region 2 of the Igf2 receptor gene and the 5′ upstream region of the H19 gene, the DMR2 region in the Igf2 gene and the 5′ region of the Xist gene becomes demethylated in undifferentiated double knockout ES cells.
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Okano M., Bell D.W., Haber D.A., Li E. DNA methylationtransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 99:1999;247-257. Inactivation of Dnmt3a and Dnmt3b in ES cells results in hypomethylation of the satellite sequences, IAP repeats and C-type retroviral DNA. Although disruption of Dnmt3a and Dnmt3b does not influence methylation within region 2 of the Igf2 receptor gene and the 5′ upstream region of the H19 gene, the DMR2 region in the Igf2 gene and the 5′ region of the Xist gene becomes demethylated in undifferentiated double knockout ES cells.
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Okano, M.1
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This paper shows that the constitutive abnormality of the genomic methylation pattern in ICF syndrome is the consequence of DNMT3B mutations. This reveals one of the specific targets of DNTM3B and indicates that DNMT3A cannot fully complement the function of DNMT3B.
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Xu G-L., Bestor T.H., Bourc'his D., Hsieh C-L., Tommerup N., Hulten M., Ou A., Russo J.J., Viegas-Pequignot E. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature. 402:1999;187-191. This paper shows that the constitutive abnormality of the genomic methylation pattern in ICF syndrome is the consequence of DNMT3B mutations. This reveals one of the specific targets of DNTM3B and indicates that DNMT3A cannot fully complement the function of DNMT3B.
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Nature
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Xu, G.-L.1
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The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome
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The human DNA methyltransferases (DNMTs) 1, 3a and 3b: Coordinate mRNA expression in normal tissues and overexpression in tumors
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Nuclear extracts of chicken embryos promote an active demethylation of DNA by excision repair of 5-methyldeoxycytidine
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Analysis of putative Rnase sensitivity and protease insensitivity of demethylation activity in extracts from rat myoblasts
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This study ruled out that a demethylase activity previously reported to be a ribozyme (see [7]) involves an RNA cofactor or a ribozyme component. The importance of this paper is to clarify that the demethylase is most likely a protein.
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Swisher J.F., Rand E., Cedar H., Marie Pyle A. Analysis of putative Rnase sensitivity and protease insensitivity of demethylation activity in extracts from rat myoblasts. Nucleic Acids Res. 26:1998;5573-5580. This study ruled out that a demethylase activity previously reported to be a ribozyme (see [7]) involves an RNA cofactor or a ribozyme component. The importance of this paper is to clarify that the demethylase is most likely a protein.
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MBD2 is a transcriptional repressor belonging to the MeCP1 histon deacetylase complex
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Ng, H.-H.1
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Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation
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Mi-2 from Xenopus is part of a histone deacetylase complex that contains three subunits. One of the subunits, p35, has similarity to mammalian MBD3 and MBD2. The Mi-2 complex is found to have no demethylase activity.
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Wade P.A., Gegonne A., Jones P.L., Ballestar E., Aubry F., Wolffe A.P. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat Genet. 23:1999;62-66. Mi-2 from Xenopus is part of a histone deacetylase complex that contains three subunits. One of the subunits, p35, has similarity to mammalian MBD3 and MBD2. The Mi-2 complex is found to have no demethylase activity.
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Nat Genet
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Wade, P.A.1
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An embryonic demethylation mechanism involving binding of transcription factors to replicating DNA
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Evidence that protein binding specifies sites of DNA demethylation
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Demethylation sites within the oriP region are specified by EBNA-1 binding. Demethylation of the first strand involves a replication-dependent pathway, and the second strand demethylation appears to involve an active demethylase.
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Hsieh C-L. Evidence that protein binding specifies sites of DNA demethylation. Mol Cell Biol. 19:1999;46-56. Demethylation sites within the oriP region are specified by EBNA-1 binding. Demethylation of the first strand involves a replication-dependent pathway, and the second strand demethylation appears to involve an active demethylase.
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Modulation of DNA binding protein affinity directly affects target site demethylation
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in press. This paper further supports the hypothesis that demethylation in human cells is initiated by specific DNA-binding proteins. The possibility of transcriptional effects is also ruled out. By titrating the binding protein in the system, this study showed for the first time that demethylation at DNA sites can be determined by the protein binding site occupancy.
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Lin I.P., Tomzynski T.J., Ou Q., Hsieh C-L. Modulation of DNA binding protein affinity directly affects target site demethylation. Mol Cell Biol. 2000;. in press. This paper further supports the hypothesis that demethylation in human cells is initiated by specific DNA-binding proteins. The possibility of transcriptional effects is also ruled out. By titrating the binding protein in the system, this study showed for the first time that demethylation at DNA sites can be determined by the protein binding site occupancy.
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Mol Cell Biol
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Lin, I.P.1
Tomzynski, T.J.2
Ou, Q.3
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Chromosome methylation patterns during mammalian preimplantation development
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Rougier N., Bourc'his D., Gomes D.M., Niveleau A., Plachot M., Paldi A., Viegas-Pequignot E. Chromosome methylation patterns during mammalian preimplantation development. Genes Dev. 12:1998;2108-2113.
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Maternal and paternal chromosomes are compartmentalized during early embryogenesis and demethylation of these two sets of chromosomes occurs at different times via different mechanisms. The concept of how the methylation pattern is established in the preimplantation stage may be changed if the findings in this study are confirmed.
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Mayer W., Niveleau A., Walter J., Fundele R., Haaf T. Demethylation of the zygotic paternal genome. Nature. 403:2000;501-502. Maternal and paternal chromosomes are compartmentalized during early embryogenesis and demethylation of these two sets of chromosomes occurs at different times via different mechanisms. The concept of how the methylation pattern is established in the preimplantation stage may be changed if the findings in this study are confirmed.
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Nature
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The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites
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The methyl-CpG binding domain of MBD4 preferentially binds to the deaminated product of methyl-CpG. MBD4 can remove thymine or uracil from a CpG site with mismatches generated either by cytosine deamination or by methyl-cytosine deamination in vitro. It is suggested that MBD4 may be responsible for eliminating mutations at methyl-CpG sites.
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Hendrich B., Hardeland U., Ng H-H., Jiricny J., Bird A. The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. Nature. 401:1999;301-304. The methyl-CpG binding domain of MBD4 preferentially binds to the deaminated product of methyl-CpG. MBD4 can remove thymine or uracil from a CpG site with mismatches generated either by cytosine deamination or by methyl-cytosine deamination in vitro. It is suggested that MBD4 may be responsible for eliminating mutations at methyl-CpG sites.
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Nature
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Hendrich, B.1
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Bird, A.5
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