In vitro selection was used to define sequence contexts that significantly enhanced the mutagenic potential of 7,8-dihydro-8-oxoguanine (8-oxoG). Contexts that simultaneously reduced the efficiency of 8-oxoG cleavage by formamidopyrimidine DNA N-glycosylase and increased the efficiency of misincorporating A opposite the lesion by DNA polymerase were isolated from a pool of 48 random octanucleotide sequences. Kinetic analysis showed that the combined effects of poor repair and high miscoding resulted in 102- to 103-fold increase in the mutagenic potential of 8-oxoG. Furthermore, the isolated sequence contexts correlated strongly with G → T transversion hotspots in spontaneous mutational spectra reported for the Escherichia coli lad and human p53 and factor IX genes. We present an example directly linking the interplay between DNA repair and replication to a 'high risk sequence' for base substitution.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Jul 21 1998|
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