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Mutagenic potential of 8-oxo-7,8-dihydroguanine depends on the location of a single strand break within a cluster

Noguchi, Miho; Urushibara, Ayumi*; Yokoya, Akinari; O'Neill, P.*; Shikazono, Naoya

Ionizing radiation (IR) produces ionization and excitation along a radiation track, and generates, amongst other DNA lesions, clustered DNA damage sites in cellular DNA. Clustered DNA damage is defined as two or more lesions induced within 1-2 helical turns (10-20bp) of DNA. It has been reported that various types of SSB have a strong inhibitory effect on the excision of 8-oxo-7,8-dihydroguanine (8-oxoG) in vitro. In the present study, we used plasmid based assay in Escherichia coli to investigate the potential of SSB to influence the mutagenicity of 8-oxoG. As a model of clustered damage, we used synthesized oligonucleotides carrying an SSB and an 8-oxoG at a restriction enzyme recognition site. In single glycosylase-deficient strain mutY, the mutagenic potential of 8-oxoG was stimulated by an SSB situated on the opposite strand. This observation indicates that a SSB retards the incision of 8-oxoG by Fpg. On the other hand, when an SSB was placed in tandem with 8-oxoG on the same strand at varying separations, these tandem damage sites showed lower mutation frequency than a single 8-oxoG lesion in every strain. These results suggest that the 8-oxoG is removed, at least in part, during repair processing of the SSB. Our studies demonstrate that the mutagenic potential of 8-oxoG depends on whether the SSB is located on either the same strand or the opposite strand containing to 8-oxoG.

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