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Enhancement of Camptothecin-Induced Topoisomerase I Cleavage Complexes by the Acetaldehyde Adduct N2-ethyl-2'-deoxyguanosine

Enhancement of Camptothecin-Induced Topoisomerase I Cleavage Complexes by the Acetaldehyde Adduct N2-ethyl-2'-deoxyguanosine

Smitha Antony, Jacob A Theruvathu, P J Brooks, Diem-Thu Lesher, Matt Redinbo, Yves Pommier

Nucleic Acids Res. 2004 Oct 21;32(18):5685-92.

PMID: 15498925

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP101803036	N2-Ethyl-2′-deoxyguanosine		101803-03-6	Price

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