Position- and orientation-specific enhancement of topoisomerase I cleavage complexes by triplex DNA structures.
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.
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Smitha
S
Antony
Paola B
PB
Arimondo
Jian-Sheng
JS
Sun
Yves
Y
Pommier
D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004789:Enzyme Activation; D008958:Models, Molecular; D009690:Nucleic Acid Conformation
C051802:triplex DNA; D004247:DNA; D004264:DNA Topoisomerases, Type I