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Mutagenic potential of clustered DNA damage containing single strand break and 8-oxoGs

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

It is proposed that a single track of ionizing radiation induces clustered DNA damage sites and that their complexity increases with increasing LET. Non-DSB clustered damage is thought to contribute to the biological effects of radiation such as mutation. In this study, we have investigated the mutagenicity of clustered DNA damage containing SSB and base damage. We have used a plasmid based assay with Escherichia coli to measure the mutation frequency induced by bistranded clustered damage. As a model of clustered damage, we have synthesized oligonucleotides containing a SSB and/or 8-oxo-7,8-dihydroguanines (8-oxoGs) within the recognition site of the restriction enzyme (Alw26I). Plasmid constructs containing damaged DNA was transfected into wild-type or glycosylase-deficient strains and propagated in cells. The mutation frequency was assessed by the inability of Alw26I to cut the oligonucleotide sequence. The mutation frequency of bistranded clusters containing an 8-oxoG opposite to a second 8-oxoG 2bp apart was the highest of all the types of clusters tested in the present study. When a SSB was included in clusters containing bistranded 8-oxoGs, the mutation frequency is lower in all E. coli strains tested. These results suggest that a SSB located on the same strand to one of the 8-oxoG reduces the mutagenic potential of 8-oxoG. Our studies demonstrate that the mutagenic potential of clusters containing 8-oxoG is modified if a SSB is present within the cluster.

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