Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been recently shown that in developing chicken embryonic nuclear extracts there is a 5-methyldeoxycytidine excision repair activity (Jost, J. P. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 4684-4688). We show that in differentiating mouse myoblasts, a similar enzymatic reaction may be responsible for the genome-wide DNA demethylation (up to 50% of all CmCGG) occurring between the 3rd and 5th days of differentiation. Furthermore, in differentiating myoblasts, there is first a 50% transient decrease in DNA methyltransferase activity and a 90% drop in the rate of DNA synthesis, followed by an increase in 5-methyl-CpG endonuclease and 5-methyldeoxycytidine excision repair activities. As tested in vitro, the maximal activity of the 5-methyldeoxycytidine excision repair coincides with the maximal in vivo genome-wide DNA demethylation. We also find that 3-aminobenzamide, a potent inhibitor of ADP-ribosyltransferase, blocks the differentiation of myoblasts, the 5-methyldeoxycytidine excision repair activity, and the genome-wide demethylation.
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PMID:Transient DNA demethylation in differentiating mouse myoblasts correlates with higher activity of 5-methyldeoxycytidine excision repair. 814 2

In vivo and in vitro experiments carried out on L929 mouse fibroblasts suggested that the poly(ADP-ribosyl) ation process acts somehow as a protecting agent against full methylation of CpG dinucleotides in genomic DNA. Since CpG islands, which are found almost exclusively at the 5'-end of housekeeping genes, are rich in CpG dinucleotides, which are the target of mammalian DNA methyltransferase, we examined the possibility that the poly(ADP-ribosyl)ation reaction is involved in maintaining the unmethylated state of these DNA sequences. Experiments were conducted by two different strategies, using either methylation-dependent restriction enzymes on purified genomic DNA or a sequence-dependent restriction enzyme on an aliquot of the same DNA, previously modified by a bisulfite reaction. With the methylation-dependent restriction enzymes, it was observed that the "HpaII tiny fragments" greatly decreased when the cells were preincubated with 3-aminobenzamide, a well known inhibitor of poly(ADP-ribose) polymerase. The other experimental approach allowed us to prove that, as a consequence of the inhibition of the poly(ADP-ribosyl)ation process, an anomalous methylation pattern could be evidenced in the CpG island of the promoter fragment of the Htf9 gene, amplified from DNA obtained from fibroblasts preincubated with 3-aminobenzamide. These data confirm the hypothesis that, at least for the Htf9 promoter region, an active poly(ADP-ribosyl)ation protects the unmethylated state of the CpG island.
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PMID:The unmethylated state of CpG islands in mouse fibroblasts depends on the poly(ADP-ribosyl)ation process. 963 20

We provided evidence that competitive inhibition of poly(ADP-ribose) polymerases in mammalian cells treated with 3-aminobenzamide causes DNA hypermethylation in the genome and anomalous hypermethylation of CpG islands. The molecular mechanism(s) connecting poly(ADP-ribosyl)ation with DNA methylation is still unknown. Here we show that DNMT1 is able to bind long and branched ADP-ribose polymers in a noncovalent way. Binding of poly ADP-ribose on DNMT1 inhibits DNA methyltransferase activity. Co-immunoprecipitation reactions indicate that PARP1 and DNMT1 are associated in vivo and that in this complex PARP1 is present in its ADP-ribosylated isoform. We suggest that this complex is catalytically inefficient in DNA methylation.
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PMID:Modulation of DNMT1 activity by ADP-ribose polymers. 1563 87