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J. Biol. Chem., Vol. 276, Issue 23, 20220-20227, June 8, 2001
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From the Department of Molecular and Structural Biology, University
of Aarhus, C.F. Møllers Allé, Building 130, DK-8000, Aarhus C,
Denmark, ¶ Medizinische Poliklinik, University of Würzburg
Medical School, Klinikstrasse 6-8, Würzburg D-97070, Germany, and
All eukaryotic forms of DNA topoisomerase I
contain an extensive and highly charged N-terminal domain. This domain
contains several nuclear localization sequences and is essential for
in vivo function of the enzyme. However, so far no direct
function of the N-terminal domain in the in vitro
topoisomerase I reaction has been reported. In this study we have
compared the in vitro activities of a truncated form of
human topoisomerase I lacking amino acids 1-206 (p67) with the
full-length enzyme (p91). Using these enzyme forms, we have identified
for the first time a direct role of residues within the N-terminal
domain in modulating topoisomerase I catalysis, as revealed by
significant differences between p67 and p91 in DNA binding, cleavage,
strand rotation, and ligation. A comparison with previously published
studies showing no effect of deleting the first 174 or 190 amino acids
of topoisomerase I (Stewart, L., Ireton, G. C., and Champoux,
J. J. (1999) J. Biol. Chem. 274, 32950-32960;
Bronstein, I. B., Wynne-Jones, A., Sukhanova, A., Fleury, F.,
Ianoul, A., Holden, J. A., Alix, A. J., Dodson, G. G.,
Jardillier, J. C., Nabiev, I., and Wilkinson, A. J. (1999) Anticancer Res. 19, 317-327) suggests a pivotal role of
amino acids 191-206 in catalysis. Taken together the presented data indicate that at least part(s) of the N-terminal domain regulate(s) enzyme/DNA dynamics during relaxation most probably by controlling non-covalent DNA binding downstream of the cleavage site either directly or by coordinating DNA contacts by other parts of the enzyme.
Residues within the N-terminal Domain of Human
Topoisomerase I Play a Direct Role in Relaxation*
,
,, Section of Molecular Genetics and Microbiology, University of
Texas at Austin, Texas 78712
Present address: Dept. of Genetics and Development, College of
Physicians and Surgeons, Columbia University, 701 West 168th St., New
York, NY 10032.
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