Human abasic endonuclease action on multilesion abasic clusters: implications for radiation-induced biological damage
Abstract
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 bipolarmore »
- Authors:
-
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- National Institutes of Health (NIH), Bethesda, MD (United States)
- Publication Date:
- Research Org.:
- Brookhaven National Laboratory (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
- OSTI Identifier:
- 1625443
- Grant/Contract Number:
- SC0012704
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nucleic Acids Research
- Additional Journal Information:
- Journal Volume: 36; Journal Issue: 8; Journal ID: ISSN 0305-1048
- Publisher:
- Oxford University Press
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Biochemistry & Molecular Biology
Citation Formats
Paap, Brigitte, Wilson, David M., and Sutherland, Betsy M. Human abasic endonuclease action on multilesion abasic clusters: implications for radiation-induced biological damage. United States: N. p., 2008.
Web. doi:10.1093/nar/gkn118.
Paap, Brigitte, Wilson, David M., & Sutherland, Betsy M. Human abasic endonuclease action on multilesion abasic clusters: implications for radiation-induced biological damage. United States. https://doi.org/10.1093/nar/gkn118
Paap, Brigitte, Wilson, David M., and Sutherland, Betsy M. Wed .
"Human abasic endonuclease action on multilesion abasic clusters: implications for radiation-induced biological damage". United States. https://doi.org/10.1093/nar/gkn118. https://www.osti.gov/servlets/purl/1625443.
@article{osti_1625443,
title = {Human abasic endonuclease action on multilesion abasic clusters: implications for radiation-induced biological damage},
author = {Paap, Brigitte and Wilson, David M. and Sutherland, Betsy M.},
abstractNote = {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.},
doi = {10.1093/nar/gkn118},
journal = {Nucleic Acids Research},
number = 8,
volume = 36,
place = {United States},
year = {Wed Mar 19 00:00:00 EDT 2008},
month = {Wed Mar 19 00:00:00 EDT 2008}
}
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