Naturally mutagenic sequence diversity in a human type II topoisomerase

Author:

Bandak Afif F.1ORCID,Blower Tim R.1ORCID,Nitiss Karin C.23,Gupta Raveena23,Lau Albert Y.1,Guha Ria23,Nitiss John L.2,Berger James M.1ORCID

Affiliation:

1. Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205

2. Pharmaceutical Sciences Department, University of Illinois College of Pharmacy, Rockford, IL 61107

3. Biomedical Sciences Department, University of Illinois College of Medicine, Rockford, IL 61107

Abstract

Type II topoisomerases transiently cleave duplex DNA as part of a strand passage mechanism that helps control chromosomal organization and superstructure. Aberrant DNA cleavage can result in genomic instability, and how topoisomerase activity is controlled to prevent unwanted breaks is poorly understood. Using a genetic screen, we identified mutations in the beta isoform of human topoisomerase II (hTOP2β) that render the enzyme hypersensitive to the chemotherapeutic agent etoposide. Several of these variants were unexpectedly found to display hypercleavage behavior in vitro and to be capable of inducing cell lethality in a DNA repair–deficient background; surprisingly, a subset of these mutations were also observed in TOP2B sequences from cancer genome databases. Using molecular dynamics simulations and computational network analyses, we found that many of the mutations obtained from the screen map to interfacial points between structurally coupled elements, and that dynamical modeling could be used to identify other damage-inducing TOP2B alleles present in cancer genome databases. This work establishes that there is an innate link between DNA cleavage predisposition and sensitivity to topoisomerase II poisons, and that certain sequence variants of human type II topoisomerases found in cancer cells can act as DNA-damaging agents. Our findings underscore the potential for hTOP2β to function as a clastogen capable of generating DNA damage that may promote or support cellular transformation.

Funder

HHS | National Institutes of Health

HHS | NIH | National Cancer Institute

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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