Increased mutability and decreased repairability of a three-lesion clustered DNA-damaged site comprised of an AP site and bi-stranded 8-oxoG lesions. (June 2014)

• Record Type: Journal Article
• Authors: Cunniffe, Siobhan; Walker, Alexandra; Stabler, Robert; O'Neill, Peter; Lomax, Martine E.
• Is Part Of: International journal of radiation biology. Volume 90:Number 6(2014:Jun.)
• Page Start: 468
• Page End: 479
• Publication Date: 2014-06
• Subjects: Radiation -- Physiological effect -- Periodicals; Radiobiology -- Periodicals; 571.45
• DOI: 10.3109/09553002.2014.899449
• Languages: English
• ISSNs: 0955-3002

Abstract

<abstract> <title>Abstract</title> <p> <italic>Purpose</italic>: Ionizing radiation induces DNA damage, some of which are present in clusters, defined as two or more lesions within one to two helical turns of DNA by passage of a single radiation track. These clusters are thought to contribute to the detrimental effects of radiation, in part due to the compromised repair of clustered DNA damaged sites.</p> <p> <italic>Materials and methods</italic>: The repair of three-lesion cluster present in oligonucleotides were determined <italic>in vitro</italic> using the hamster cell line CHO-K1 nuclear extract or purified proteins involved in base excision repair. The mutagenic potential of these clusters present in a plasmid was determined using an <italic>Escherichia coli</italic> reporter assay.</p> <p> <italic>Results</italic>: We have shown that the repair of an abasic (AP) site within a three-lesion cluster, comprised of an AP site and bi-stranded 8-oxo-7, 8-dihydroguanine (8-oxoG) lesions, is retarded compared to that of an isolated AP site in an <italic>in vitro</italic> base excision repair (BER) assay. Further, the mutation frequency of the clustered damaged site is up to three times greater than that of an isolated 8-oxoG lesion.</p> <p> <italic>Conclusions</italic>: As a consequence of enhanced mutagenic potential of clusters, non-double-strand break (DSB) DNA damage may contribute to the detrimental effects of radiation, in addition to the effects of DSB.</p> </abstract>