Mechanism of mutagenesis induced by cytosine analogs bearing N(4)-substitutions.
The mechanism of mutagenesis induced by dihydropyrimido [4,5-c][1,2]oxazin-7-one deoxyriboside, P-nucleoside, was studied. This analog is highly mutagenic toward Escherichia coli and Salmonella typhimurium. In E. coli, it induces GC-to-AT and AT-to-GC transitions specifically. No transversions are inducible. P-nucleoside was highly mutagenic to a wild-type E. coli, but little mutagenic in a strain lacking thymidine kinase. This indicates that P-nucleoside may be phosphorylated by thymidine kinase after its uptake into bacteria. The mutagenesis induced by P-nucleoside was efficiently inhibited by the addition of thymidine. This inhibition further confirmed the involvement of thymidine kinase in the first step of the metabolism of P-nucleoside in the bacterial cells. These findings indicate that P-nucleoside is a mutagen of a nucleoside-analog type, causing mutations by the erroneous incorporation and replication. The experiments to prove its ambiguous nature in DNA synthesis is now under way.
Negishi
K
K
Gene Research Center, Okayama University, Japan.
Williams
D M
DM
Inoue
Y
Y
Iimura
T
T
Katahira
M
M
Kanazawa
H
H
Uesugi
S
S
Hayatsu
H
H
Brown
M D
MD
D000225:Adenine / Q000737:chemistry; D001482:Base Composition; D001665:Binding Sites; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004269:DNA, Bacterial / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006147:Guanine / Q000737:chemistry; D016296:Mutagenesis; D009153:Mutagens / Q000737:chemistry / Q000494:pharmacology*; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013937:Thymidine Kinase / Q000378:metabolism
D004269:DNA, Bacterial; D009153:Mutagens; D009705:Nucleosides; D006147:Guanine; D003596:Cytosine; D013937:Thymidine Kinase; D000225:Adenine