Published online 21 October 2004
Nucleic Acids Research, Vol. 32 No. 18 © Oxford University Press 2004; all rights reserved
Enhancement of camptothecin-induced topoisomerase I cleavage complexes by the acetaldehyde adduct N2-ethyl-2'-deoxyguanosine
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA, 1 Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-8110, USA and 2 Department of Chemistry, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
* To whom correspondence should be addressed at Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Bldg 37, Room 5068. Tel: +1 301 496 5944; Fax: +1 301 402 0752; Email: pommier{at}nih.gov
Received August 30, 2004; Revised and Accepted October 2, 2004
The activity of DNA topoisomerase I (Top1), an enzyme that regulates DNA topology, is impacted by DNA structure alterations and by the anticancer alkaloid camptothecin (CPT). Here, we evaluated the effect of the acetaldehyde-derived DNA adduct, N2-ethyl-2'-deoxyguanosine (N2-ethyl-dG), on human Top1 nicking and closing activities. Using purified recombinant Top1, we show that Top1 nicking-closing activity remains unaffected in N2-ethyl-dG adducted oligonucleotides. However, the N2-ethyl-dG adduct enhanced CPT-induced Top1–DNA cleavage complexes depending on the relative position of the N2-ethyl-dG adduct with respect to the Top1 cleavage site. The Top1-mediated DNA religation (closing) was selectively inhibited when the N2-ethyl-dG adduct was present immediately 3' from the Top1 site (position +1). In addition, when the N2-ethyl-dG adduct was located at the –5 position, CPT enhanced cleavage at an alternate Top1 cleavage site immediately adjacent to the adduct, which was then at position +1 relative to this new alternate Top1 site. Modeling studies suggest that the ethyl group on the N2-ethyl-dG adduct located at the 5' end of a Top1 site (position +1) sterically blocks the dissociation of CPT from the Top1–DNA complex, thereby inhibiting further the religation (closing) reaction.
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