1-methyladenine and 3-methylcytosine

1-methyladenine has been researched along with 3-methylcytosine* in 9 studies

Reviews

2 review(s) available for 1-methyladenine and 3-methylcytosine

ArticleYear
DNA repair by bacterial AlkB proteins.
    Research in microbiology, 2003, Volume: 154, Issue:8

    The Escherichia coli AlkB protein is an iron- and 2-oxoglutarate-dependent oxygenase, repairing 1-methyladenine and 3-methylcytosine lesions in DNA. AlkB homologues are present in a number of bacterial species, and some bacteria have two different AlkB proteins. AlkB also repairs lesions in RNA, and the biological significance of RNA repair is discussed.

    Topics: Adenine; Alkylation; Bacterial Proteins; Cytosine; DNA Repair; Escherichia coli Proteins; Mixed Function Oxygenases; Molecular Sequence Data; Oxygenases; Phylogeny; Sequence Alignment; Sequence Homology, Amino Acid

2003
DNA repair: bioinformatics helps reverse methylation damage.
    Current biology : CB, 2002, Dec-23, Volume: 12, Issue:24

    Recent work has uncovered a novel DNA repair enzyme: the AlkB protein of Escherichia coli, which oxidises the methyl groups of 1-methyladenine and 3-methylcytosine to hydroxymethyl moieties; the oxidised groups are subsequently released as formaldehyde, regenerating the unmodified bases.

    Topics: Adenine; Computational Biology; Cytosine; DNA Methylation; DNA Repair; Escherichia coli; Escherichia coli Proteins; Mixed Function Oxygenases

2002

Other Studies

7 other study(ies) available for 1-methyladenine and 3-methylcytosine

ArticleYear
AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells.
    Scientific reports, 2017, 02-13, Volume: 7

    The mammalian AlkB homolog (ALKBH) family of proteins possess a 2-oxoglutarate- and Fe(II)-dependent oxygenase domain. A similar domain in the Escherichia coli AlkB protein catalyzes the oxidative demethylation of 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) in both DNA and RNA. AlkB homolog 3 (ALKBH3) was also shown to demethylate 1-meA and 3-meC (induced in single-stranded DNA and RNA by a methylating agent) to reverse the methylation damage and retain the integrity of the DNA/RNA. We previously reported the high expression of ALKBH3 in clinical tumor specimens and its involvement in tumor progression. In this study, we found that ALKBH3 effectively demethylated 1-meA and 3-meC within endogenously methylated RNA. Moreover, using highly purified recombinant ALKBH3, we identified N6-methyladenine (N6-meA) in mammalian transfer RNA (tRNA) as a novel ALKBH3 substrate. An in vitro translation assay showed that ALKBH3-demethylated tRNA significantly enhanced protein translation efficiency. In addition, ALKBH3 knockdown in human cancer cells impaired cellular proliferation and suppressed the nascent protein synthesis that is usually accompanied by accumulation of the methylated RNAs. Thus, our data highlight a novel role for ALKBH3 in tumor progression via RNA demethylation and subsequent protein synthesis promotion.

    Topics: Adenine; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; AlkB Homolog 5, RNA Demethylase; Animals; Cattle; Cell Line, Tumor; Cytosine; Demethylation; Gene Knockdown Techniques; Humans; Methylation; Pancreatic Neoplasms; Protein Biosynthesis; Recombinant Proteins; RNA, Transfer; Substrate Specificity

2017
Enzymological and structural studies of the mechanism of promiscuous substrate recognition by the oxidative DNA repair enzyme AlkB.
    Proceedings of the National Academy of Sciences of the United States of America, 2009, Aug-25, Volume: 106, Issue:34

    Promiscuous substrate recognition, the ability to catalyze transformations of chemically diverse compounds, is an evolutionarily advantageous, but poorly understood phenomenon. The promiscuity of DNA repair enzymes is particularly important, because it enables diverse kinds of damage to different nucleotide bases to be repaired in a metabolically parsimonious manner. We present enzymological and crystallographic studies of the mechanisms underlying promiscuous substrate recognition by Escherichia coli AlkB, a DNA repair enzyme that removes methyl adducts and some larger alkylation lesions from endocyclic positions on purine and pyrimidine bases. In vitro Michaelis-Menten analyses on a series of alkylated bases show high activity in repairing N1-methyladenine (m1A) and N3-methylcytosine (m3C), comparatively low activity in repairing 1,N(6)-ethenoadenine, and no detectable activity in repairing N1-methylguanine or N3-methylthymine. AlkB has a substantially higher k(cat) and K(m) for m3C compared with m1A. Therefore, the enzyme maintains similar net activity on the chemically distinct substrates by increasing the turnover rate of the substrate with nominally lower affinity. Cocrystal structures provide insight into the structural basis of this "k(cat)/K(m) compensation," which makes a significant contribution to promiscuous substrate recognition by AlkB. In analyzing a large ensemble of crystal structures solved in the course of these studies, we observed 2 discrete global conformations of AlkB differing in the accessibility of a tunnel hypothesized to control diffusion of the O(2) substrate into the active site. Steric interactions between a series of protein loops control this conformational transition and present a plausible mechanism for preventing O(2) binding before nucleotide substrate binding.

    Topics: Adenine; Catalysis; Catalytic Domain; Crystallography, X-Ray; Cytosine; DNA Repair; DNA, Bacterial; Escherichia coli; Escherichia coli Proteins; Guanosine; Kinetics; Mixed Function Oxygenases; Models, Molecular; Molecular Structure; Oxidation-Reduction; Oxygen; Protein Conformation; Protein Structure, Tertiary; Substrate Specificity; Thymine

2009
Repair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA.
    The EMBO journal, 2006, May-17, Volume: 25, Issue:10

    Two human homologs of the Escherichia coli AlkB protein, denoted hABH2 and hABH3, were recently shown to directly reverse 1-methyladenine (1meA) and 3-methylcytosine (3meC) damages in DNA. We demonstrate that mice lacking functional mABH2 or mABH3 genes, or both, are viable and without overt phenotypes. Neither were histopathological changes observed in the gene-targeted mice. However, in the absence of any exogenous exposure to methylating agents, mice lacking mABH2, but not mABH3 defective mice, accumulate significant levels of 1meA in the genome, suggesting the presence of a biologically relevant endogenous source of methylating agent. Furthermore, embryonal fibroblasts from mABH2-deficient mice are unable to remove methyl methane sulfate (MMS)-induced 1meA from genomic DNA and display increased cytotoxicity after MMS exposure. In agreement with these results, we found that in vitro repair of 1meA and 3meC in double-stranded DNA by nuclear extracts depended primarily, if not solely, on mABH2. Our data suggest that mABH2 and mABH3 have different roles in the defense against alkylating agents.

    Topics: Adenine; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; Alleles; Animals; Cell Line; Cytosine; Dioxygenases; DNA; DNA Repair; DNA Repair Enzymes; DNA-Binding Proteins; Female; Humans; Male; Mice; Mice, Knockout; Molecular Structure; Tissue Distribution

2006
Bioinformatic mapping of AlkB homology domains in viruses.
    BMC genomics, 2005, Jan-03, Volume: 6

    AlkB-like proteins are members of the 2-oxoglutarate- and Fe(II)-dependent oxygenase superfamily. In Escherichia coli the protein protects RNA and DNA against damage from methylating agents. 1-methyladenine and 3-methylcytosine are repaired by oxidative demethylation and direct reversal of the methylated base back to its unmethylated form. Genes for AlkB homologues are widespread in nature, and Eukaryotes often have several genes coding for AlkB-like proteins. Similar domains have also been observed in certain plant viruses. The function of the viral domain is unknown, but it has been suggested that it may be involved in protecting the virus against the post-transcriptional gene silencing (PTGS) system found in plants. We wanted to do a phylogenomic mapping of viral AlkB-like domains as a basis for analysing functional aspects of these domains, because this could have some relevance for understanding possible alternative roles of AlkB homologues e.g. in Eukaryotes.. Profile-based searches of protein sequence libraries showed that AlkB-like domains are found in at least 22 different single-stranded RNA positive-strand plant viruses, but mainly in a subgroup of the Flexiviridae family. Sequence analysis indicated that the AlkB domains probably are functionally conserved, and that they most likely have been integrated relatively recently into several viral genomes at geographically distinct locations. This pattern seems to be more consistent with increased environmental pressure, e.g. from methylating pesticides, than with interaction with the PTGS system.. The AlkB domain found in viral genomes is most likely a conventional DNA/RNA repair domain that protects the viral RNA genome against methylating compounds from the environment.

    Topics: Adenine; Amino Acid Sequence; Chromosome Mapping; Computational Biology; Cytosine; DNA Damage; DNA Methylation; DNA Repair; Escherichia coli; Escherichia coli Proteins; Genome, Viral; Genomics; Humans; Methylation; Mixed Function Oxygenases; Molecular Sequence Data; Oxygen; Phylogeny; Protein Structure, Tertiary; RNA; Sequence Analysis, DNA; Sequence Homology, Amino Acid

2005
Demethylation of 3-methylthymine in DNA by bacterial and human DNA dioxygenases.
    The Journal of biological chemistry, 2004, Sep-24, Volume: 279, Issue:39

    Rare DNA lesions that are chemically stable and refractory to repair may add disproportionately to the accumulation of mutations in long lived cells. 3-Methylthymine is a minor lesion that is induced by DNA-methylating agents and for which no repair process has been described previously. Here we demonstrate that this lesion can be directly demethylated in vitro by bacterial and human DNA dioxygenases. The Escherichia coli AlkB and human ABH3 proteins repaired 3-methylthymine in both single-stranded and double-stranded polydeoxynucleotides, whereas the human ABH2 protein preferred a duplex substrate. Thus, the known substrates of these enzymes now include 3-methylthymine in DNA, as well as 1-methyladenine and 3-methylcytosine, which all have structurally similar sites of alkylation. Repair of 3-methylthymine by AlkB and ABH3 was optimal at pH 6, but inefficient. At physiological pH, 3-methylthymine, which is a minor methylated lesion, was more slowly repaired than the major lesion generated in single-stranded DNA, 3-methylcytosine. Our data suggest that 3-methylthymine residues in DNA will be repaired inefficiently in vivo and therefore may occur at a low steady-state level, but the residues should not gradually accumulate to high levels in long lived cells.

    Topics: Adenine; Binding Sites; Chromatography, High Pressure Liquid; Cytosine; DNA; DNA Methylation; DNA Repair; DNA, Single-Stranded; Dose-Response Relationship, Drug; Escherichia coli; Humans; Hydrogen-Ion Concentration; Mixed Function Oxygenases; Models, Chemical; Polymers; Thymine; Time Factors

2004
Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage.
    Nature, 2002, Sep-12, Volume: 419, Issue:6903

    Methylating agents generate cytotoxic and mutagenic DNA damage. Cells use 3-methyladenine-DNA glycosylases to excise some methylated bases from DNA, and suicidal O(6)-methylguanine-DNA methyltransferases to transfer alkyl groups from other lesions onto a cysteine residue. Here we report that the highly conserved AlkB protein repairs DNA alkylation damage by means of an unprecedented mechanism. AlkB has no detectable nuclease, DNA glycosylase or methyltransferase activity; however, Escherichia coli alkB mutants are defective in processing methylation damage generated in single-stranded DNA. Theoretical protein fold recognition had suggested that AlkB resembles the Fe(ii)- and alpha-ketoglutarate-dependent dioxygenases, which use iron-oxo intermediates to oxidize chemically inert compounds. We show here that purified AlkB repairs the cytotoxic lesions 1-methyladenine and 3-methylcytosine in single- and double-stranded DNA in a reaction that is dependent on oxygen, alpha-ketoglutarate and Fe(ii). The AlkB enzyme couples oxidative decarboxylation of alpha-ketoglutarate to the hydroxylation of these methylated bases in DNA, resulting in direct reversion to the unmodified base and the release of formaldehyde.

    Topics: Adenine; Alkylation; Chromatography, High Pressure Liquid; Cytosine; DNA Damage; DNA Methylation; DNA Repair; DNA, Bacterial; DNA, Single-Stranded; Edetic Acid; Escherichia coli; Escherichia coli Proteins; Ethanol; Formaldehyde; Gas Chromatography-Mass Spectrometry; Hydroxylation; Mixed Function Oxygenases; Mutation; Oxidation-Reduction; Oxygen

2002
Reversal of DNA alkylation damage by two human dioxygenases.
    Proceedings of the National Academy of Sciences of the United States of America, 2002, Dec-24, Volume: 99, Issue:26

    The Escherichia coli AlkB protein protects against the cytotoxicity of methylating agents by repair of the DNA lesions 1-methyladenine and 3-methylcytosine, which are generated in single-stranded stretches of DNA. AlkB is an alpha-ketoglutarate- and Fe(II)-dependent dioxygenase that oxidizes the relevant methyl groups and releases them as formaldehyde. Here, we identify two human AlkB homologs, ABH2 and ABH3, by sequence and fold similarity, functional assays, and complementation of the E. coli alkB mutant phenotype. The levels of their mRNAs do not appear to correlate with cell proliferation but tissue distributions are different. Both enzymes remove 1-methyladenine and 3-methylcytosine from methylated polynucleotides in an alpha-ketoglutarate-dependent reaction, and act by direct damage reversal with the regeneration of the unsubstituted bases. AlkB, ABH2, and ABH3 can also repair 1-ethyladenine residues in DNA with the release of acetaldehyde.

    Topics: Adenine; AlkB Homolog 1, Histone H2a Dioxygenase; Alkylation; Amino Acid Sequence; Cytosine; DNA Damage; DNA Repair; DNA Repair Enzymes; Escherichia coli Proteins; Humans; Mixed Function Oxygenases; Molecular Sequence Data

2002
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