Dissecting de novo methylation.
Nature Genetics (impact factor: 35.53). 01/2000; 23(4):380-2. DOI:10.1038/70476 pp.380-2
Article: Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair.[show abstract] [hide abstract]
ABSTRACT: While methylcytosines serve as the fifth base encoding epigenetic information, they are also a dangerous endogenous mutagen due to their intrinsic instability. Methylcytosine undergoes spontaneous deamination, at a rate much higher than cytosine, to generate thymine. In mammals, two repair enzymes, thymine DNA glycosylase (TDG) and methyl-CpG binding domain 4 (MBD4), have evolved to counteract the mutagenic effect of methylcytosines. Both recognize G/T mismatches arising from methylcytosine deamination and initiate base-excision repair that corrects them to G/C pairs. However, the mechanism by which the methylation status of the repaired cytosines is restored has remained unknown. We show here that the DNA methyltransferase Dnmt3a interacts with TDG. Both the PWWP domain and the catalytic domain of Dnmt3a are able to mediate the interaction with TDG at its N-terminus. The interaction affects the enzymatic activity of both proteins: Dnmt3a positively regulates the glycosylase activity of TDG, while TDG inhibits the methylation activity of Dnmt3a in vitro. These data suggest a mechanistic link between DNA repair and remethylation at sites affected by methylcytosine deamination.Nucleic Acids Research 02/2007; 35(2):390-400. · 8.03 Impact Factor
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ABSTRACT: Hypermethylation of cell cycle regulators and increased DNA methyltransferase 1 (Dnmt1) mRNA level have been reported in hepatocarcinogenesis. However, the expression of Dnmts has not yet been examined in hepatocellular carcinomas (HCCs). We examined 13 cases of HCCs in dysplastic nodules (DNs) and 28 cases of advanced HCCs for Dnmt1 and Dnmt3a, and compared the results with those of 9 cases of low-grade DNs, 24 cases of high-grade DNs, and 59 cases of nonneoplastic liver tissues from 59 cases of surgically resected livers by immunohistochemical staining. Nuclear expression of Dnmt1 was increased significantly in all HCCs in DNs and advanced HCCs compared with those of nonneoplastic livers, low-grade DNs, and high-grade DNs (P <0.05). Nuclear expression of Dnmt3a was not detectable in nonneoplastic liver and low-grade DN, whereas it was observed in high-grade DNs (7 of 24, 29.2%), HCCs in DNs (7 of 13, 53.8%), and advanced HCCs (11 of 28, 39.3%). Different from Dnmt1 immunostaining, cytoplasmic immunoreactivity for Dmnt3a was significantly decreased or absent in 13 of 24 cases of high-grade DNs (54.1%), 12 of 13 cases of HCCs in DNs (92.3%), and 22 of 28 cases of advanced HCCs (78.6%), compared with nonneoplastic livers and low-grade DNs (P <0.05). Our data suggest that Dnmt1 and Dnmt3a play a role in the early stage of hepatocarcinogenesis and that dysregulation of Dnmt3a may be involved in the progression of HCC. Furthermore, the significantly decreased cytoplasmic immunoreactivity for Dnmt3a in high-grade DNs and HCCs can be used as a diagnostic adjunct.Human Pathlogy 01/2003; 34(1):11-7. · 2.88 Impact Factor
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