Paradoxical role of the major DNA repair protein, OGG1, in action-at-a-distance mutation induction by 8-oxo-7,8-dihydroguanine

Oxidatively damaged bases induce mutations and are involved in cancer initiation. 8-Oxo-7,8-dihydroguanine (G°, 8-hydroxyguanine) is an abundant oxidized base that induces targeted G:C→T:A transversions in human cells, as well as untargeted base substitution (action-at-a-distance) mutations of the G bases of 5′-GpA-3′ dinucleotides. The action-at-a-distance mutations become more frequent than the targeted transversions when the amount of Werner syndrome (WRN) protein is decreased. In this study, OGG1, the major DNA glycosylase for the damaged base, and WRN were knocked down in isolation and in combination in human U2OS cells, and a shuttle plasmid carrying G° was introduced into the knockdown cells. Interestingly, fewer action-at-a-distance mutations were observed in the WRN plus OGG1 double knockdown cells, as compared to the WRN single knockdown cells. These results indicated the paradoxical role of OGG1, as an accelerator of the action-at-a-distance mutations by the oxidized guanine base. •8-Oxo-7,8-dihydroguanine induces untargeted base substitution mutations.•OGG1 is the major DNA glycosylase for the oxidized base.•Knockdown of Werner syndrome (WRN) protein enhances the untargeted mutations.•OGG1 knockdown suppresses the increase in the mutations by the WRN reduction.•The paradoxical role of OGG1 in the untargeted mutations is indicated.