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Human abasic endonuclease action on multilesion abasic clusters: implications for radiation-induced biological damage

Journal Article · · Nucleic Acids Research
DOI:https://doi.org/10.1093/nar/gkn118· OSTI ID:1625443
 [1];  [2];  [3]
  1. Brookhaven National Lab. (BNL), Upton, NY (United States); DOE/OSTI
  2. National Institutes of Health (NIH), Bethesda, MD (United States)
  3. Brookhaven National Lab. (BNL), Upton, NY (United States)
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Clustered damages—two or more closely opposed abasic sites, oxidized bases or strand breaks—are induced in DNA by ionizing radiation and by some radiomimetic drugs. They are potentially mutagenic or lethal. High complexity, multilesion clusters (three or more lesions) are hypothesized as repairresistant and responsible for the greater biological damage induced by high linear energy transfer radiation (e.g. charged particles) than by low linear energy transfer X- or γ-rays. We tested this hypothesis by assessing human abasic endonuclease Ape1 activity on two- and multiple-lesion abasic clusters. We constructed cluster-containing oligonucleotides using a central variable cassette with abasic site(s) at specific locations, and 5’ and 3’ terminal segments tagged with visually distinctive fluorophores. The results indicate that in two- or multiple-lesion clusters, the spatial arrangement of uni-sided positive [in which the opposing strand lesion(s) is 3’ to the base opposite the reference lesion)] or negative polarity [opposing strand lesion(s) 5’ to the base opposite the reference lesion] abasic clusters is key in determining Ape1 cleavage efficiency. However, no bipolar clusters (minimally three-lesions) were good Ape1 substrates. The data suggest an underlying molecular mechanism for the higher levels of biological damage associated with agents producing complex clusters: the induction of highly repair-resistant bipolar clusters.
Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
SC0012704
OSTI ID:
1625443
Journal Information:
Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 8 Vol. 36; ISSN 0305-1048
Publisher:
Oxford University PressCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (10)

Delayed repair of radiation induced clustered DNA damage: Friend or foe? journal June 2011
Nucleotide Excision Repair of Chemically Stabilized Analogues of DNA Interstrand Cross-Links Produced from Oxidized Abasic Sites journal September 2014
Hierarchy of lesion processing governs the repair, double-strand break formation and mutability of three-lesion clustered DNA damage journal December 2009
Replication fork collapse is a major cause of the high mutation frequency at three-base lesion clusters journal August 2013
Clustered DNA Lesions Containing 5-Formyluracil and AP Site: Repair via the BER System journal August 2013
Increased mutability and decreased repairability of a three-lesion clustered DNA-damaged site comprised of an AP site and bi-stranded 8-oxoG lesions journal April 2014
Fractionated Radiation Exposure of Rat Spinal Cords Leads to Latent NeuroInflammation in Brain, Cognitive Deficits, and Alterations in Apurinic Endonuclease 1 text January 2015
Rapid DNA-protein cross-linking and strand scission by an abasic site in a nucleosome core particle journal December 2010
The Yield, Processing, and Biological Consequences of Clustered DNA Damage Induced by Ionizing Radiation journal January 2009
Fractionated Radiation Exposure of Rat Spinal Cords Leads to Latent Neuro-Inflammation in Brain, Cognitive Deficits, and Alterations in Apurinic Endonuclease 1 journal July 2015

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