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PMID: 15469908 Published · epublish English Journal Article

Position- and orientation-specific enhancement of topoisomerase I cleavage complexes by triplex DNA structures.

Nucleic acids research ·Vol. 32 ·No. 17 ·2004-00-00 ·Pages 5163-73

Antony S, Arimondo PB, Sun JS, Pommier Y

Abstract

Topoisomerase I (Top1) activities are sensitive to various endogenous base modifications, and anticancer drugs including the natural alkaloid camptothecin. Here, we show that triple helix-forming oligonucleotides (TFOs) can enhance Top1-mediated DNA cleavage by affecting either or both the nicking and the closing activities of Top1 depending on the position and the orientation of the triplex DNA structure relative to the Top1 site. TFO binding 1 bp downstream from the Top1 site enhances cleavage by inhibiting religation and to a lesser extent DNA nicking. In contrast, TFO binding 4 bp downstream from the Top1 site enhances DNA nicking especially when the 3' end of the TFO is proximal to the Top1 site. However, when the orientation of the triplex is inverted, with its 5' terminus 4 bp downstream from the Top1 site, religation is also inhibited. These position- and orientation-dependent effects of triplex structures on the Top1-mediated DNA cleavage and religation are discussed in the context of molecular modeling and effects of TFO on DNA twist and mobility at the duplex/triplex junction.

MeSH Terms
Base Sequence DNA/chemistry,metabolism DNA Topoisomerases, Type I/metabolism Enzyme Activation Models, Molecular Nucleic Acid Conformation
Chemicals
triplex DNA DNA DNA Topoisomerases, Type I
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Antony Smitha
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Arimondo Paola B
Sun Jian-Sheng
Pommier Yves
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
Published
2004-00-00
Epub
2004-00-04
Pages
5163-73
Language
English
Region
England
NLM ID
0411011
PMCID
PMC521660
Subset
IM
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