Oxidized, deaminated cytosines are a source of C --> T transitions in vivo.
The most common base substitution arising from oxidative damage of DNA is a GC --> AT transition. In an effort to determine the oxidized lesion(s) that gives rise to this mutation, the mutagenicity of three oxidized cytosines, 5-hydroxycytosine, 5-hydroxyuracil, and uracil glycol, were investigated in Escherichia coli. An M13 viral genome was constructed to contain a single oxidized cytosine at a specific site. Replication in vivo of the single-stranded genomes yielded mutation frequencies of 0.05%, 83%, and 80% for 5-hydroxycytosine, 5-hydroxyuracil, and uracil glycol, respectively. The predominant mutation observed was C --> T. A model for C --> T oxidative mutagenesis is suggested in which initial cytosine oxidation is followed by deamination to a poorly repaired uracil derivative that is strongly miscoding during replication.
Kreutzer
D A
DA
Division of Toxicology and Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Essigmann
J M
JM
D003596:Cytosine; D004249:DNA Damage; D004261:DNA Replication; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli; D016679:Genome, Viral; D016296:Mutagenesis; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics
D004279:DNA, Viral; D003596:Cytosine