Methylation cytosine

The reaction mechanism of the DNA (cytosine-5)-methyltransferase-catalyzed cytosine methylation was investigated at the MP2 and DFT levels [98JA12895]. This system has been modeled by 1-methylcytosine 117, methylthiolate, and trimethylsulfonium. The cytosine methylation is initiated by an attack of the anionic methylthiolate at Cg of the cytosine ring (Scheme 77). The formation of the methylthiolate adduct 118 of the neutral 117 was found to be endothermic in the gas phase and in solution. However, the MP2 and DFT results differ... 

Yoder JA, Walsh CP, Bestor TH (1997) Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 13 335-340... 

In fact, the cross-talk between histone methylation and DNA methylation has been experimentally demonstrated for the first time in Neurospora [145] (see commentary by Bird [146]) and proved the second scenario. Using the power of Neurospora genetics, Tamaru and Selker [145] have identified a gene which, when mutated, abolishes methylation of all tested DNA sequences. This gene, dim-5, is different from dim-2, the previously identified gene that encodes the only DNA methyltransferase in Neurospora responsible for all known cytosine methylation in this fungus. The dim-5 gene encodes a histone H3 methyltransferase the deduced polypeptide sequence contains a SET domain with sequence similarity to some known histone methyltransferases moreover, the recombinant DIM-5 protein exhibits histone methyltransferase activity in vitro. Additional in vivo experiments... 

Watt, F. and Molloy, P.L. (1988) Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. Genes and Development, 2, 1136-1143. 

CS-cytosine methylation of DNA mechanistic implications of new ystal structures for HhaL methyitransferase-DNA-AdoHcy complexes. Journal of Molecular Biology, 261 (5), 634-645. 

Figure8.5 Mechanism of cytosine methylation. For a description see text. AdoHcy S-Adenosylhomocysteine.

Mass, M.J. and Wang, L. (1997) Arsenic alters cytosine methylation patterns of the promoter of the tumor suppressor gene p53 in human lung cells a model for a mechanism of carcinogenesis. Mutation Research-Reviews in Mutation Research, 386(3), 263-77. 

The biologic processes described above and cytosine methylation, fit the epigenetic definition well because they are heritable. However, whether the entire repertoire of histone modifications is heritable remains to be established. In fact, it is likely that only a subset will have epigenetic inheritance. 

Perakyla M. A model study of the enzyme-catalyzed cytosine methylation using ab initio quantum mechanical and density functional theory calculations pKa of the cytosine N3 in the intermediates and transition states of the reaction. J. Amer. Chem. Soc. 1998 120 12895-12902. 

Another major form of base damage generated in DNA by UV light is one in which the C6 position of a 5 pyrimidine is covalently linked to the C4 position of the 3 adjacent pyrimidine (Fig. 6). These lesions [which are readily detected by their lability in alkaline conditions at 80-100° C (43)], are called pyrimidine-pyrimidone [6-4] adducts, or simply [6-4] photoproducts ([6-4]PP). The pyrimidine planes in ([6-4]PP) are almost perpendicular. Hence, they result in prominent distortions of the double-helical structure of DNA. ([6-4]PP) can involve adjacent TC, CC, or (less often) TT sequences. Their formation at CT sequences is infrequent. Cytosine methylation at the C5 position inhibits the formation of [6-4]PP (44). The yield of [6-4]PP is proportional to the incident UV fluence in the range 100-500 J/m and continues to increase after exposure to several thousand J/m (1). In UV-C irradiated DNA, the ratio of CPD [6-4]PP is 3 1 (1). 

Banda ru, B., Gopal, J., and Bhagwat, A. S. (1996). O erprr>duction of DNA cytosine methyl-trairsferases causes methylatLon and C-T mutations at nrm-canonkal sites. /. Biol. Orem. 271, 78S1-7B59. 

After the four bases have been incorporated into DNA, they can be modified by methylation, the addition of methyl groups at various positions (Figure 23-5). The bases that are most frequently methylated are guanine and cytosine. Methylation of cytosine residues influences gene regulation in higher organisms, and about 70% of GC base pairs in mammalian cells are methylated. The pattern of methylation of cytosine residues is inherited and is specific... 

In human tumors, the pattern of p53 mutations is dominated by base transitions (C to T or G to A) at CpG dinucleotides (23% of all mutations). Although this type of mutation has been observed at 35 different codons, 90% of human CpG transitions are at one of six hotspot codons 175,213,245, 248, 273 and 282 (Fig. 3A) known to be important in maintaining p53 biological activity. CpG dinucleotides are sites of cytosine methylation, and deamination of 5-methylcytosine producing thymine is the most characteristic event generating spontaneous mutations in mammalian cells (Barker et... 

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