Abstract
Nucleolin functions in ribosome biogenesis and contains an acidic N terminus that binds nuclear localization sequences. In previous work we showed that human nucleolin associates with the N-terminal region of human topoisomerase I (Top1). We have now mapped the topoisomerase I interaction domain of nucleolin to the N-terminal 225 amino acids. We also show that the Saccharomyces cerevisiae nucleolin ortholog, Nsr1p, physically interacts with yeast topoisomerase I, yTop1p. Studies of isogenic NSR1(+) and Deltansr1 strains indicate that NSR1 is important in determining the cellular localization of yTop1p. Moreover, deletion of NSR1 reduces sensitivity to camptothecin, an antineoplastic topoisomerase I inhibitor. By contrast, Deltansr1 cells are hypersensitive to the topoisomerase II-targeting drug amsacrine. These findings indicate that nucleolin/Nsr1 is involved in the cellular localization of Top1 and that this localization may be important in determining sensitivity to drugs that target topoisomerases.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amsacrine / pharmacology
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Antineoplastic Agents / pharmacology
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Camptothecin / pharmacology
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Cell Division / genetics
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DNA Topoisomerases, Type I / metabolism*
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DNA Topoisomerases, Type II / metabolism
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Drug Resistance, Microbial / genetics
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Fungal Proteins / chemistry
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Fungal Proteins / genetics
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Fungal Proteins / metabolism*
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Humans
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Microbial Sensitivity Tests
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Microscopy, Fluorescence
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Mutation
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Nuclear Proteins*
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Protein Binding
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Protein Structure, Tertiary
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Protein Transport
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RNA-Binding Proteins*
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Recombinant Fusion Proteins / metabolism
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Saccharomyces cerevisiae / enzymology*
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism*
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Saccharomyces cerevisiae Proteins*
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Subcellular Fractions / chemistry
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Topoisomerase I Inhibitors
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Topoisomerase II Inhibitors
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Transformation, Genetic
Substances
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Antineoplastic Agents
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Fungal Proteins
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NSR1 protein, S cerevisiae
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Nuclear Proteins
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RNA-Binding Proteins
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Recombinant Fusion Proteins
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Saccharomyces cerevisiae Proteins
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Topoisomerase I Inhibitors
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Topoisomerase II Inhibitors
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Amsacrine
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DNA Topoisomerases, Type I
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DNA Topoisomerases, Type II
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Camptothecin