Journal
DNA REPAIR
Volume 111, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.dnarep.2022.103276
Keywords
8-Oxo-7,8-dihydroguanine; 8-Hydroxyguanine; Action-at-a-distance mutation; OGG1; Werner syndrome protein; APOBEC3
Categories
Funding
- Japan Society for the Pro-motion of Science (JSPS) KAKENHI [JP 16H02956, JP 19H04278, JP 17K12824, JP 20K12181]
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Oxidatively damaged bases can induce mutations, and 8-hydroxyguanine is a common oxidized base that can cause targeted and untargeted base substitution mutations. The frequency of untargeted mutations increases when the Werner syndrome protein is decreased. In this study, knocking down both OGG1 and WRN resulted in fewer untargeted mutations compared to knocking down WRN alone, suggesting the paradoxical role of OGG1 in accelerating untargeted mutations caused by oxidized guanine base.
Oxidatively damaged bases induce mutations and are involved in cancer initiation. 8-Oxo-7,8-dihydroguanine (G degrees, 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 degrees 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.
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