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Direct Monitoring of the Strand Passage Reaction of DNA Topoisomerase II Triggers Checkpoint Activation

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      Abstract

      By necessity, the ancient activity of type II topoisomerases co-evolved with the double-helical structure of DNA, at least in organisms with circular genomes. In humans, the strand passage reaction of DNA topoisomerase II (Topo II) is the target of several major classes of cancer drugs which both poison Topo II and activate cell cycle checkpoint controls. It is important to know the cellular effects of molecules that target Topo II, but the mechanisms of checkpoint activation that respond to Topo II dysfunction are not well understood. Here, we provide evidence that a checkpoint mechanism monitors the strand passage reaction of Topo II. In contrast, cells do not become checkpoint arrested in the presence of the aberrant DNA topologies, such as hyper-catenation, that arise in the absence of Topo II activity. An overall reduction in Topo II activity (i.e. slow strand passage cycles) does not activate the checkpoint, but specific defects in the T-segment transit step of the strand passage reaction do induce a cell cycle delay. Furthermore, the cell cycle delay depends on the divergent and catalytically inert C-terminal region of Topo II, indicating that transmission of a checkpoint signal may occur via the C-terminus. Other, well characterized, mitotic checkpoints detect DNA lesions or monitor unattached kinetochores; these defects arise via failures in a variety of cell processes. In contrast, we have described the first example of a distinct category of checkpoint mechanism that monitors the catalytic cycle of a single specific enzyme in order to determine when chromosome segregation can proceed faithfully.

      Author Summary

      Several major classes of anti-cancer drugs kill tumor cells by binding to the enzyme DNA topoisomerase II, but at the same time, cellular responses are activated that protect the tumor cells. How checkpoint activation occurs under circumstances of topoisomerase II perturbation is not well understood. We show that a novel checkpoint mechanism directly monitors the enzyme reaction of topoisomerase II. This is the first example of a checkpoint mechanism that directly monitors specific steps of the catalytic cycle of a single enzyme.

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      Most cited references 44

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      Cellular roles of DNA topoisomerases: a molecular perspective.

      DNA topoisomerases are the magicians of the DNA world by allowing DNA strands or double helices to pass through each other, they can solve all of the topological problems of DNA in replication, transcription and other cellular transactions. Extensive biochemical and structural studies over the past three decades have provided molecular models of how the various subfamilies of DNA topoisomerase manipulate DNA. In this review, the cellular roles of these enzymes are examined from a molecular point of view.
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        Targeting DNA topoisomerase II in cancer chemotherapy.

         John Nitiss (2009)
        Recent molecular studies have expanded the biological contexts in which topoisomerase II (TOP2) has crucial functions, including DNA replication, transcription and chromosome segregation. Although the biological functions of TOP2 are important for ensuring genomic integrity, the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy. The molecular tools that have allowed an understanding of the biological functions of TOP2 are also being applied to understanding the details of drug action. These studies promise refined targeting of TOP2 as an effective anticancer strategy.
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          Aneuploidy and isochromosome formation in drug-resistant Candida albicans.

          Resistance to the limited number of available antifungal drugs is a serious problem in the treatment of Candida albicans. We found that aneuploidy in general and a specific segmental aneuploidy, consisting of an isochromosome composed of the two left arms of chromosome 5, were associated with azole resistance. The isochromosome forms around a single centromere flanked by an inverted repeat and was found as an independent chromosome or fused at the telomere to a full-length homolog of chromosome 5. Increases and decreases in drug resistance were strongly associated with gain and loss of this isochromosome, which bears genes expressing the enzyme in the ergosterol pathway targeted by azole drugs, efflux pumps, and a transcription factor that positively regulates a subset of efflux pump genes.
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            Author and article information

            Affiliations
            [1 ]Department of Genetics, Cell Biology & Development, University of Minnesota, Minneapolis, Minnesota, United States of America
            [2 ]Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
            Stowers Institute for Medical Research, United States of America
            Author notes

            The authors have declared that no competing interests exist.

            Conceived and designed the experiments: KLF DJC ACV HJT JAWB NO. Performed the experiments: KLF WSH ABL HJT JAWB DJC. Analyzed the data: KLF DJC ABL ACV HJT JAWB NO. Contributed reagents/materials/analysis tools: KLF DJC ACV ABL HJT JAWB NO. Wrote the paper: KLF DJC HJT JAWB NO.

            Contributors
            Role: Editor
            Journal
            PLoS Genet
            PLoS Genet
            plos
            plosgen
            PLoS Genetics
            Public Library of Science (San Francisco, USA )
            1553-7390
            1553-7404
            October 2013
            October 2013
            3 October 2013
            : 9
            : 10
            3789831
            PGENETICS-D-12-00015
            10.1371/journal.pgen.1003832
            (Editor)

            This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Counts
            Pages: 20
            Funding
            This work was partly funded by NSF grant MCB-0842157 (DJC) and NIH grant GM033944 (NO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article

            Genetics

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