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Induction of topoisomerase I cleavage complexes by 1-beta -D-arabinofuranosylcytosine (ara-C) in vitro and in ara-C-treated cells

Abstract : 1-beta-d-Arabinofuranosylcytosine (Ara-C) is a nucleoside analog commonly used in the treatment of leukemias. Ara-C inhibits DNA polymerases and can be incorporated into DNA. Its mechanism of cytotoxicity is not fully understood. Using oligonucleotides and purified human topoisomerase I (top1), we found a 4- to 6-fold enhancement of top1 cleavage complexes when ara-C was incorporated at the +1 position (immediately 3') relative to a unique top1 cleavage site. This enhancement was primarily due to a reversible inhibition of top1-mediated DNA religation. Because ara-C incorporation is known to alter base stacking and sugar puckering at the misincorporation site and at the neighboring base pairs, the observed inhibition of religation at the ara-C site suggests the importance of the alignment of the 5'-hydroxyl end for religation with the phosphate group of the top1 phosphotyrosine bond. This study also demonstrates that ara-C treatment and DNA incorporation trap top1 cleavage complexes in human leukemia cells. Finally, we report that camptothecin-resistant mouse P388/CPT45 cells with no detectable top1 are crossresistant to ara-C, which suggests that top1 poisoning is a potential mechanism for ara-C cytotoxicity.
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https://www.hal.inserm.fr/inserm-02438285
Contributor : Philippe Pourquier <>
Submitted on : Tuesday, January 14, 2020 - 10:45:41 AM
Last modification on : Wednesday, July 15, 2020 - 10:26:01 AM

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P. Pourquier, Y. Takebayashi, Y. Urasaki, C. Gioffre, G. Kohlhagen, et al.. Induction of topoisomerase I cleavage complexes by 1-beta -D-arabinofuranosylcytosine (ara-C) in vitro and in ara-C-treated cells. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2000, 97 (4), pp.1885-1890. ⟨10.1073/pnas.97.4.1885⟩. ⟨inserm-02438285⟩

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