Regulation of DNA Topology by Topoisomerases: Mathematics at the Molecular Level

Getting stressed over topoisomerase I poisons

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Topoisomerase I is the target for a number of widely prescribed anticancer drugs that are based on camptothecin. In this issue of Cell Chemical Biology, Flor et al demonstrate that the cellular response to camptothecin is mediated by lipid-derived electrophiles that are generated as a result of drug-induced oxidative stress.DNA topoisomerases are enzymes that regulate DNA underwinding (i.e., negative supercoiling) and overwinding (i.e., positive supercoiling) (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier et al, 2016). These enzymes relieve the torsional strain caused by the accumulation of positive DNA supercoils ahead of replication and transcription complexes and the accumulation of negative supercoils behind transcription complexes (Figure 1) by making transient breaks in the nucleic acid backbone (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier, 2013).

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“…Topoisomerase I plays an important role in alleviating this strain in human cells. The enzyme removes positive and negative supercoils by generating a single-stranded break in the double helix and allowing controlled rotation about the break (Ashley and Osheroff, 2019;Pommier, 2013). Human topoisomerase IIα and IIβ also play critical roles in alleviating torsional and axial (knotting and tangling) strain in DNA.…”

“…These latter enzymes act by generating a double-stranded break in the genetic material and passing a separate double helix through the break (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier, 2013).Beyond their critical cellular functions, human topoisomerases are the targets for some of the most widely prescribed anticancer drugs worldwide (Deweese and Osheroff, 2009;Ketron and Osheroff, 2014;Pommier, 2009Pommier, , 2013. The article by Flor et al (Flor et al, 2021) in this issue of Cell Chemical Biology draws an important link between the actions of drugs that target topoisomerase I and oxidative stress in treated cells.Topoisomerase-targeted anticancer drugs rely on the fact that these enzymes generate DNA strand breaks by the nucleophilic attack of active site tyrosine residues on the sugar phosphate backbone of the double helix (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier, 2013). In order to maintain genomic integrity during DNA cleavage, topoisomerases covalently attach to the newly generated DNA termini through the formation of phosphotyrosine bonds.…”

“…DNA topoisomerases are enzymes that regulate DNA underwinding (i.e., negative supercoiling) and overwinding (i.e., positive supercoiling) (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier et al, 2016). These enzymes relieve the torsional strain caused by the accumulation of positive DNA supercoils ahead of replication and transcription complexes and the accumulation of negative supercoils behind transcription complexes (Figure 1) by making transient breaks in the nucleic acid backbone (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier, 2013). Topoisomerase I plays an important role in alleviating this strain in human cells.…”

“…Human topoisomerase IIα and IIβ also play critical roles in alleviating torsional and axial (knotting and tangling) strain in DNA. These latter enzymes act by generating a double-stranded break in the genetic material and passing a separate double helix through the break (Ashley and Osheroff, 2019;Deweese and Osheroff, 2009;Pommier, 2013).…”