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Nucleic Acids Research Advance Access published online on March 19, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn118
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

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

Brigitte Paap1, David M. Wilson, III2 and Betsy M. Sutherland1,*

1Biology Department, Brookhaven National Laboratory, Upton, NY 11973-5000 and 2Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA

*To whom correspondence should be addressed. Tel: 631 344-3380; Fax: 631 344-3407; Email: bms{at}bnl.gov

Received November 23, 2007. Revised February 28, 2008. Accepted February 29, 2008.

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 repair-resistant 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 {gamma}-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.

Present address: Brigitte Paap, Center for Functional Nanobioscience, Biodesign Institute, Arizona State University, 1001 S. McAllister Ave., PO Box 875001, Tempe, AZ 85287-5001 and High Throughput Genomics, Inc., 6296 East Grant Road, Tucson, AZ 85712, USA


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