The geometry of DNA supercoils modulates topoisomerase-mediated DNA cleavage and enzyme response to anticancer drugs

Biochemistry
A Kathleen McClendon, Neil Osheroff

Abstract

Collisions with DNA tracking systems are critical for the conversion of transient topoisomerase-DNA cleavage complexes to permanent strand breaks. Since DNA is overwound ahead of tracking systems, cleavage complexes most likely to produce permanent strand breaks should be formed between topoisomerases and positively supercoiled molecules. Therefore, the ability of human topoisomerase IIalpha and IIbeta and topoisomerase I to cleave positively supercoiled DNA was assessed in the absence or presence of anticancer drugs. Topoisomerase IIalpha and IIbeta maintained approximately 4-fold lower levels of cleavage complexes with positively rather than negatively supercoiled DNA. Topoisomerase IIalpha also displayed lower levels of cleavage with overwound substrates in the presence of nonintercalative drugs. Decreased drug efficacy was due primarily to a drop in baseline (i.e., nondrug) cleavage, rather than an altered interaction with the enzyme-DNA complex. Similar results were seen for topoisomerase IIbeta, but the effects of DNA geometry on drug-induced scission were somewhat less pronounced. With both topoisomerase IIalpha and IIbeta, intercalative drugs displayed greater relative cleavage enhancement with positively supercoiled DN...Continue Reading

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Citations

Aug 30, 2008·Quarterly Reviews of Biophysics·Allyn J Schoeffler, James M Berger
Dec 13, 2016·Biophysics Reviews·Yeonee Seol, Keir C Neuman
Mar 16, 2019·International Journal of Molecular Sciences·Melissa Antoniou-KourouniotiChristine J Farr
Feb 24, 2007·The Journal of Antimicrobial Chemotherapy·Bokun ChengYuk-Ching Tse-Dinh
Oct 18, 2008·Nature Protocols·Thomas S Dexheimer, Yves Pommier
Sep 22, 2010·Nucleic Acids Research·Amanda C GentryNeil Osheroff
May 17, 2017·Biophysics Reviews·Yeonee Seol, Keir C Neuman
Sep 22, 2017·Nucleic Acids Research·Rachel E AshleyNeil Osheroff
May 21, 2020·Molecular Cancer Therapeutics·Laetitia MarziYves Pommier
Aug 8, 2007·Mutation Research·A Kathleen McClendon, Neil Osheroff
Feb 7, 2012·Biochemistry·Adam C KetronNeil Osheroff
May 11, 2018·ACS Infectious Diseases·Elizabeth G GibsonNeil Osheroff
Sep 30, 2021·Nature Communications·Jonathan M FoggLynn Zechiedrich
Jun 15, 2010·Structure·Lynn Zechiedrich, Neil Osheroff

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