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Human DNA Topoisomerase I: Structure, Enzymology and Biology

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DNA Topoisomerases and Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Human topoisomerase I (Top1) catalyzes the reversible cleavage of one strand of DNA to provide swivels to relax the supercoils associated with DNA replication, transcription, and chromatin assembly. The cleavage reaction occurs with the covalent attachment of an active-site tyrosine to the 3′ end of the broken strand; religation restores continuity to the DNA and releases the enzyme. During the cleaved state, relaxation of torsionally strained supercoils occurs by a controlled rotation mechanism. X-ray crystal structures of the enzyme with bound DNA combined with single-molecule experiments provide insights into the chemistry, specificity, and dynamics of the DNA relaxation process. A failure of Top1 to carry out religation at DNA lesions or in the presence of drugs such as camptothecin causes DNA damage that must be repaired if the cell is to survive. The list of proteins known to interact with Top1 suggests that the enzyme has functions in vivo that extend well beyond the previously characterized roles in replication, transcription, and chromatin assembly.

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Acknowledgments

The author gratefully acknowledges Sharon Schultz and Zheng Yang for help during the preparation of the manuscript. This work was supported by National Institutes of Health Grant GM049156.

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  1. Department of Microbiology, School of Medicine, University of Washington, Health Sciences Bldg, 1959 N.E. Pacific Street, 98195, 357735, Seattle, WA, USA

    James J. Champoux

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Correspondence to James J. Champoux .

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  1. Laboratory of Molecular Pharmacology, National Institutes of Health Laboratory of Molecular Pharmacology, Bethesda, Maryland, USA

    Yves Pommier

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Champoux, J.J. (2012). Human DNA Topoisomerase I: Structure, Enzymology and Biology. In: Pommier, Y. (eds) DNA Topoisomerases and Cancer. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0323-4_2

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  • DOI: https://doi.org/10.1007/978-1-4614-0323-4_2

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