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Topoisomerase Inhibition and Torsional Stress

Topoisomerase Inhibition and Torsional Stress

Topology is critical in allowing chromatin to function in a normal manner. DNA templating is clearly impacted when enzymes that relieve strain are blocked in a chromatin context. Specifically, inhibition of topoisomerases leads to rapid accumulation of torsional strain accompanied by changes in Pol II kinetics and destabilization of nucleosomes.

Transcription-generated torsional stress destabilizes nucleosomes

Article Source: Nature

Abstract
As RNA polymerase II (Pol II) transcribes a gene, it encounters an array of well-ordered nucleosomes. How it traverses through this array in vivo remains unresolved. One model proposes that torsional stress generated during transcription destabilizes nucleosomes ahead of Pol II. Here, we describe a method for high-resolution mapping of underwound DNA, using next-generation sequencing, and show that torsion is correlated with gene expression in Drosophila melanogaster cells. Accumulation of torsional stress, through topoisomerase inhibition, results in increased Pol II at transcription start sites. Whereas topoisomerase I inhibition results in increased nascent RNA transcripts, topoisomerase II inhibition causes little change. Despite the different effects on Pol II elongation, topoisomerase inhibition results in increased nucleosome turnover and salt solubility within gene bodies, thus suggesting that the elongation-independent effects of torsional stress on nucleosome dynamics contributes to the destabilization of nucleosomes.

Nature Structural & Molecular Biology 21, 88–94 (2014) doi:10.1038/nsmb.2723

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