Abstract
Ionizing radiation induces clustered DNA damage where two or more lesions are located proximal to each other on the same or opposite DNA strands. It has been suggested that individual lesions within a cluster are removed sequentially and that the presence of a vicinal lesion(s) may affect the rate and fidelity of DNA repair. In this study, we addressed the question of how 8-oxoguanine located opposite to normal or reduced abasic sites would affect the repair of these sites by the base excision repair system. We have found that an 8-oxoguanine located opposite to an abasic site does not affect either the efficiency or fidelity of repair synthesis by DNA polymerase beta. In contrast, an 8-oxoguanine located one nucleotide 3'-downstream of the abasic site significantly reduces both strand displacement synthesis supported by DNA polymerase beta or delta and cleavage by flap endonuclease of the generated flap, thus inhibiting the long-patch base excision repair pathway.
Highlights
Ionizing radiation induces clustered DNA damage where two or more lesions are located proximal to each other on the same or opposite DNA strands
It was earlier proposed that a high density of hydroxyl radicals induced by irradiation may induce multiple closely spaced DNA lesions [23], until recently these lesions were considered as regular oxidative lesions that can be repaired by Base excision repair (BER)
Studies indicated that the complexity of clustered DNA lesions poses a significant challenge to repair systems and may cause infidelity of repair, resulting in mutations and inefficient repair that could potentially lead to the formation of deletions and chromosome rearrangements [27,28,29,30]
Summary
An 8-oxoguanine located one nucleotide 3-downstream of the abasic site significantly reduces both strand displacement synthesis supported by DNA polymerase  or ␦ and cleavage by flap endonuclease of the generated flap, inhibiting the long-patch base excision repair pathway. BER involves several steps, i.e. removal of a damaged base by a DNA glycosylase, nicking of an AP site by AP endonuclease, repair synthesis, and the sealing of the nick by DNA ligase [8] All of these reactions may be affected by the presence of a neighboring lesion. We have employed oligonucleotide duplexes containing 8-oxoguanine located either directly opposite or one nucleotide 3Ј to an SSB containing a 3Ј-OH end and either a normal or reduced 5Ј-sugar phosphate end Using these substrates and purified human BER proteins, we characterized the effect of 8-oxoguanine on the repair of clustered lesions via short- and long-patch BER
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