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Chiral discrimination and writhe-dependent relaxation mechanism of human topoisomerase IIα. | LitMetric

Chiral discrimination and writhe-dependent relaxation mechanism of human topoisomerase IIα.

J Biol Chem

Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Published: May 2013

AI Article Synopsis

  • Human topoisomerase IIα is crucial for managing DNA supercoils and unlinking chromosomes, primarily by relaxing positive supercoils; this process is influenced by factors like supercoil chirality, twist density, and DNA tension.
  • Findings from single-molecule experiments indicate that the enzyme's relaxation rate depends on how effectively the topoisomerase C-terminal domains capture the DNA segment during the strand passage process.
  • The study highlights the intricate mechanism of chiral discrimination in supercoil relaxation by htopo IIα and suggests that variations in DNA tension or twist can affect this process, ultimately impacting the enzyme's efficiency in strand passage.

Article Abstract

Background: Human topoisomerase IIα unlinks catenated chromosomes and preferentially relaxes positive supercoils.

Results: Supercoil chirality, twist density, and tension determine topoisomerase IIα relaxation rate and processivity.

Conclusion: Strand passage rate is determined by the efficiency of transfer segment capture that is modulated by the topoisomerase C-terminal domains.

Significance: Single-molecule measurements reveal the mechanism of chiral discrimination and tension dependence of supercoil relaxation by human topoisomerase IIα. Type IIA topoisomerases (Topo IIA) are essential enzymes that relax DNA supercoils and remove links joining replicated chromosomes. Human topoisomerase IIα (htopo IIα), one of two human isoforms, preferentially relaxes positive supercoils, a feature shared with Escherichia coli topoisomerase IV (Topo IV). The mechanistic basis of this chiral discrimination remains unresolved. To address this important issue, we measured the relaxation of individual supercoiled and "braided" DNA molecules by htopo IIα using a magnetic tweezers-based single-molecule assay. Our study confirmed the chiral discrimination activity of htopo IIα and revealed that the strand passage rate depends on DNA twist, tension on the DNA, and the C-terminal domain (CTD). Similar to Topo IV, chiral discrimination by htopo IIα results from chiral interactions of the CTDs with DNA writhe. In contrast to Topo IV, however, these interactions lead to chiral differences in relaxation rate rather than processivity. Increasing tension or twist disrupts the CTD-DNA interactions with a subsequent loss of chiral discrimination. Together, these results suggest that transfer segment (T-segment) capture is the rate-limiting step in the strand passage cycle. We propose a model for T-segment capture that provides a mechanistic basis for chiral discrimination and provides a coherent explanation for the effects of DNA twist and tension on eukaryotic type IIA topoisomerases.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650406PMC
http://dx.doi.org/10.1074/jbc.M112.444745DOI Listing

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