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5-Methylcytosine

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Richard H. Fish – One of the best experts on this subject based on the ideXlab platform.

Didier Wion – One of the best experts on this subject based on the ideXlab platform.

Sei-ichi Nishimoto – One of the best experts on this subject based on the ideXlab platform.

Mariappan Vairapandi – One of the best experts on this subject based on the ideXlab platform.

  • PARTIAL PURIFICATION AND CHARACTERIZATION OF HUMAN 5-Methylcytosine-DNA GLYCOSYLASE
    Oncogene, 1996
    Co-Authors: Mariappan Vairapandi
    Abstract:

    The molecular mechanisms by which DNA 5-Methylcytosine content is modulated are incompletely understood. Reduction of DNA 5-Methylcytosine content has been correlated with the transition from hyperplasia to adenoma in the genesis of human adenocarcinoma of the colon. 5-Methylcytosine-DNA glycosylase removes 5-Methylcytosine from DNA as a free base, but its involvement in this process is unknown. The 5-Methylcytosine-DNA glycosylase activity in HeLa nuclear extracts has been partially purified, with a 460-fold enrichment, and characterized. This activity is specific for 5-Methylcytosine at CpG sites in fully methylated DNA; hemimethylated DNA is not a significant substrate. DNA containing unmethylated cytosines is not cleaved by the enzyme. There is an absolute requirement for Mg2+ ions for the activity, which is inhibited by EDTA. This 5-Methylcytosine-DNA glycosylase activity could be involved in carcinogenesis, transcription, replication, differentiation and development through resultant DNA hypomethylation following enzymatic removal of 5-Methylcytosine from DNA.

  • Excision of ultraviolet-induced photoproducts of 5-Methylcytosine from DNA.
    Mutation research, 1994
    Co-Authors: Mariappan Vairapandi, Nahum J. Duker
    Abstract:

    Transition mutations at DNA 5-Methylcytosines, congregated at CpG islands, are implicated in the etiogenesis of human diseases. Formation of 5-Methylcytosine hydrate (5-methyl-6-hydroxy-5,6-dihydrocytosine) by hydration of the 5,6 double bond of 5-Methylcytosine has been suggested as an intermediate in a possible mechanism of deamination to thymine. Ultraviolet irrairradiation of DNA yields pyrimidine hydrates, which are removed by repair glycosylases. We have identified 5-Methylcytosine photoproducts following their excision from DNA by E. coli endonuclease III. Poly(dG-[3H]5-medC):poly(dG-[3H]5-medC) was irradiated and reacted with the enzyme. Radiolabeled photoproduct releases were directly proportional to irradiation doses and enzyme concentrations. These were identified as cis-thymine hydrate (6-hydroxy-5,6-dihydrothymine) and trans-thymine hydrate. Recovery of thymine hydrates is consistent with hydration of pyrimidines. Subsequent heating (which converts thymine hydrates to thymines) and chemical sequencing of an irradiated, 3′ end-labeled, synthetic DNA<DNA strand demonstrated the appearance of thymine at the 5-Methylcytosine site. These results demonstrate a mechanism for deamination of DNA 5-Methylcytosine via hydration of the 5,6 double bond, putatively yielding 5-Methylcytosine hydrate; this deaminates to thymine hydrate, and loss of water yields thymine formation at the 5-Methylcytosine site. Identification of these DNA 5-Methylcytosine modified moieties indicates a possible molecular mechanism for the frequent transition mutations found at CpG loci.

  • Enzymic removal of 5-Methylcytosine from DNA by a human DNA-glycosylase
    Nucleic Acids Research, 1993
    Co-Authors: Mariappan Vairapandi, Nahum J. Duker
    Abstract:

    Abstract DNA 5-Methylcytosine is a major factor in the silencing of mammalian genes; it is involved in gene expression, differentiation, embryogenesis and neoplastic transformation. A decrease in DNA 5-Methylcytosine content is associated with activation of specific genes. There is much evidence indicating this to be an enzymic process, with replacement of 5-Methylcytosine by cytosine. We demonstrate here enzymic release of 5-Methylcytosines from DNA by a human 5-Methylcytosine-DNA glycosylase activity, which affords a possible mechanism for such replacement. This activity generates promutagenic apyrimidinic sites, which can be related to the high frequency of mutations found at DNA 5-Methylcytosine loci. The recovery of most released pyrimidines as thymines indicates subsequent deamination of free 5-Methylcytosines by a 5-Methylcytosine deaminase activity. This prevents possible recycling of 5-Methylcytosine into replicative DNA synthesis via a possible 5-methyl-dCTP intermediate synthesized through the pyrimidine salvage pathway. Taken together, these findings indicate mechanisms for removal of 5-Methylcytosines from DNA, hypermutability of DNA 5-Methylcytosine sites, and exclusion of 5-Methylcytosines from DNA during replication.

David Ratel – One of the best experts on this subject based on the ideXlab platform.

  • undetectable levels of n6 methyl adenine in mouse dna cloning and analysis of pred28 a gene coding for a putative mammalian dna adenine methyltransferase
    FEBS Letters, 2006
    Co-Authors: David Ratel, Jean-luc Ravanat, Mariepierre Charles, Nadine Platet, Lionel Breuillaud, Joel Lunardi, François Berger, Didier Wion
    Abstract:

    Three methylated bases, 5-Methylcytosine, N4-methylcytosine and N6-methyladenine (m6A), can be found in DNA. However, to date, only 5-Methylcytosine has been detected in mammalian genomes. To reinvestigate the presence of m6A in mammalian DNA, we used a highly sensitive method capable of detecting one N6-methyldeoxyadenosine per million nucleosides. Our results suggest that the total mouse genome contains, if any, less than 10 3 m6A. Experiments were next performed on PRED28, a putative mammalian N6-DNA methyltransferase. The murine PRED28 encodes two alternatively spliced RNA. However, although recombinant PRED28 proteins are found in the nucleus, no evidence for an adenine-methyltransferase activity was detected.

  • undetectable levels of n6 methyl adenine in mouse dna cloning and analysis of pred28 a gene coding for a putative mammalian dna adenine methyltransferase
    FEBS Letters, 2006
    Co-Authors: David Ratel, Jean-luc Ravanat, Mariepierre Charles, Nadine Platet, Lionel Breuillaud, Joel Lunardi, François Berger, Didier Wion
    Abstract:

    Three methylated bases, 5-Methylcytosine, N4-methylcytosine and N6-methyladenine (m6A), can be found in DNA. However, to date, only 5-Methylcytosine has been detected in mammalian genomes. To reinvestigate the presence of m6A in mammalian DNA, we used a highly sensitive method capable of detecting one N6-methyldeoxyadenosine per million nucleosides. Our results suggest that the total mouse genome contains, if any, less than 10 3 m6A. Experiments were next performed on PRED28, a putative mammalian N6-DNA methyltransferase. The murine PRED28 encodes two alternatively spliced RNA. However, although recombinant PRED28 proteins are found in the nucleus, no evidence for an adenine-methyltransferase activity was detected.