Structural highlights
Function
[TOP2A_HUMAN] Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes.[1]
Publication Abstract from PubMed
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-A-resolution structure of the DNA cleavage core of human topoisomerase IIalpha (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 IIbeta (TOP2B) suggests possible modification points for developing paralog-specific inhibitors to overcome the tendency of topoisomerase II-targeting chemotherapeutics to generate secondary malignancies.
The Structure of DNA-Bound Human Topoisomerase II Alpha: Conformational Mechanisms for Coordinating Inter-Subunit Interactions with DNA Cleavage.,Wendorff TJ, Schmidt BH, Heslop P, Austin CA, Berger JM J Mol Biol. 2012 Dec 7;424(3-4):109-24. doi: 10.1016/j.jmb.2012.07.014. Epub 2012, Jul 25. PMID:22841979[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lee S, Jung SR, Heo K, Byl JA, Deweese JE, Osheroff N, Hohng S. DNA cleavage and opening reactions of human topoisomerase IIalpha are regulated via Mg2+-mediated dynamic bending of gate-DNA. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2925-30. doi:, 10.1073/pnas.1115704109. Epub 2012 Feb 9. PMID:22323612 doi:http://dx.doi.org/10.1073/pnas.1115704109
- ↑ Wendorff TJ, Schmidt BH, Heslop P, Austin CA, Berger JM. The Structure of DNA-Bound Human Topoisomerase II Alpha: Conformational Mechanisms for Coordinating Inter-Subunit Interactions with DNA Cleavage. J Mol Biol. 2012 Dec 7;424(3-4):109-24. doi: 10.1016/j.jmb.2012.07.014. Epub 2012, Jul 25. PMID:22841979 doi:http://dx.doi.org/10.1016/j.jmb.2012.07.014
