Nucleic Acids Research Advance Access originally published online on September 20, 2006
Nucleic Acids Research 2006 34(18):5093-5100; doi:10.1093/nar/gkl670
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Nucleic Acids Research, 2006, Vol. 34, No. 18 5093-5100
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Nucleic Acid Enzymes |
The different cleavage DNA sequence specificity explains the camptothecin resistance of the human topoisomerase I Glu418Lys mutant
1 CNR National Research Council, University of Rome Tor Vergata Via Della Ricerca Scientifica, Rome 00133, Italy 2 INFM National Institute for the Physics of Matter, University of Rome Tor Vergata Via Della Ricerca Scientifica, Rome 00133, Italy 3 Department of Biology, University of Rome Tor Vergata Via Della Ricerca Scientifica, Rome 00133, Italy 4 CASPUR Interuniversities Consortium for Supercomputing Applications, Via dei Tizii 6b Rome 00185, Italy 5 Department of Biology, University of Padua Via U. Bassi 58/B, Padua 35131, Italy
*To whom correspondence should be addressed. Tel: +39 0672594376; Fax: +39 0672594326; Email: desideri{at}uniroma2.it
Received August 17, 2006. Accepted September 1, 2006.
Yeast cells expressing the Glu418Lys human topoisomerase I mutant display a camptothecin resistance that slowly decreases as a function of time. Molecular characterization of the single steps of the catalytic cycle of the purified mutant indicates that it has a relaxation activity identical to the wild-type protein but a different DNA sequence specificity for the cleavage sites when compared to the wild-type enzyme, as assayed on several substrates. In particular the mutant has a low specificity for CPT sensitive cleavable sites. In fact, the mutant has, at variance of the wild-type enzyme, a reduced preference for cleavage sites having a thymine base in position –1 of the scissile strand. This preference, together with the strict requirement for a thymine base in position –1 for an efficient camptothecin binding, explains the temporary camptothecin resistance of the yeast cell expressing the mutant and points out the importance of the DNA sequence in the binding of the camptothecin drug.
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