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The Structure of DNA-Bound Human Topoisomerase II Alpha: Conformational Mechanisms for Coordinating Inter-Subunit Interactions with DNA Cleavage

Lookup NU author(s): Pauline Heslop, Professor Caroline AustinORCiD


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Type II topoisomerases are required for the management of DNA superhelicity and chromosome segregation, and serve as frontline targets for a variety of small-molecule therapeutics. To better understand how these enzymes act in both contexts, we determined the 2.9-angstrom-resolution structure of the DNA cleavage core of human topoisomerase II alpha (TOP2A) bound to a doubly nicked, 30-bp duplex oligonucleotide. In accord with prior biochemical and structural studies, TOP2A significantly bends its DNA substrate using a bipartite, nucleolytic center formed at an N-terminal dimerization interface of the cleavage core. However, the protein also adopts a global conformation in which the second of its two inter-protomer contact points, one at the C-terminus, has separated. This finding, together with comparative structural analyses, reveals that the principal site of DNA engagement undergoes highly quantized conformational transitions between distinct binding, cleavage, and drug-inhibited states that correlate with the control of subunit-subunit interactions. Additional consideration of our TOP2A model in light of an etoposide-inhibited complex of human topoisomerase II beta (TOP2B) suggests possible modification points for developing paralog-specific inhibitors to overcome the tendency of topoisomerase II-targeting chemotherapeutics to generate secondary malignancies. (C) 2012 Elsevier Ltd. All rights reserved.

Publication metadata

Author(s): Wendorff TJ, Schmidt BH, Heslop P, Austin CA, Berger JM

Publication type: Article

Publication status: Published

Journal: Journal of Molecular Biology

Year: 2012

Volume: 424

Issue: 3-4

Pages: 109-124

Print publication date: 07/12/2012

ISSN (print): 0022-2836

ISSN (electronic):

Publisher: Academic Press


DOI: 10.1016/j.jmb.2012.07.014


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Funder referenceFunder name
07038Leukaemia Lymphoma Research grant
CA077373National Cancer Institute
DGE 1106400National Science Foundation