Journal
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
Volume 762, Issue -, Pages 32-39Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrfmmm.2014.02.005
Keywords
Clustered DNA damage; Base excision repair; Mutation; Oxidized abasic sites; 2-Deoxyribonolactone; 8-Oxo-7,8-dihydro-2 '-deoxyguanosine
Funding
- National Institute of General Medical Science [GM-063028]
- Medical Research Council, UK [MC_PC_12001]
- MRC [MC_PC_12001] Funding Source: UKRI
- Medical Research Council [MC_PC_12001] Funding Source: researchfish
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A signature of ionizing radiation is the induction of DNA clustered damaged sites. Non-double strand break (DSB) clustered damage has been shown to compromise the base excision repair pathway, extending the lifetimes of the lesions within the cluster, compared to isolated lesions. This increases the likelihood the lesions persist to replication and thus increasing the mutagenic potential of the lesions within the cluster. Lesions formed by ionizing radiation include 8-oxo-7,8-dihydro-2 '-deoxyguanosine (8-oxodGuo) and 2-deoxyribonolactone (dL). dL poses an additional challenge to the cell as it is not repaired by the short-patch base excision repair pathway. Here we show recalcitrant dL repair is reflected in mutations observed when DNA containing it and a proximal 8-oxodGuo is replicated in Escherichia coli. 8-oxodGuo in close proximity to dL on the opposing DNA strand results in an enhanced frequency of mutation of the lesions within the cluster and a 20 base sequence flanking the clustered damage site in an E. coli based plasmid assay. In vitro repair of a dL lesion is reduced when compared to the repair of an abasic (AP) site and a tetrahydrofuran (THF), and this is due mainly to a reduction in the activity of polymerase 13, leading to retarded FEN1 and ligase 1 activities. This study has given insights in to the biological effects of clusters containing dL. (C) 2014 The Authors. Published by Elsevier B.V.
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