Special Issue "DNA Topoisomerases in Biology and Medicine"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 September 2019).

Special Issue Editors

Prof. Lynn Zechiedrich
E-Mail Website
Guest Editor
Kyle and Josephine Morrow Chair and Professor in Molecular Virology and Microbiology; Verna and Marrs McLean Department of Biochemistry and Molecular Biology; Department of Pharmacology and Chemical Biology; Baylor College of Medicine; Houston, TX USA
Dr. Keir C. Neuman
E-Mail Website
Guest Editor
Laboratory of Single Molecule Biophysics, NHLBI

Special Issue Information

Dear Colleagues,

A community of researchers has convened at three conferences on DNA Topoisomerases in Biology and Medicine over the past six years. With new connections revealed by new discoveries, the field has both broadened and advanced significantly. The application of new methods in chromosome-wide analyses, single-molecule approaches, rigorous quantitative modeling, large human cancer datasets, improved imaging techniques, and more reveal that the topoisomerases carry out far more functions—both positive and negative—in cells than was previously appreciated. This Special Issue serves to summarize the discoveries revealed at the biennial Conferences on DNA Topoisomerases in Biology and Medicine and to hint at what is to come in 2020. In it, we will capture the spirit of these intense, highly cooperative, and multidisciplinary meetings to put the diverse array of highly related topics and approaches together in one place. We envision a Special Issue such as this one being published in advance of each meeting led by the chair or co-chairs of the next meeting.

Prof. Lynn Zechiedrich
Dr. Keir C. Neuman
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • DNA structure and function
  • DNA topology
  • DNA supercoiling
  • DNA/genome stability/instability, repair, and recombination
  • DNA metabolism
  • Drug resistance in cancer
  • Evolution of topoisomerases
  • Fluoroquinolone resistance
  • Non-B DNA structures
  • Topoisomerase structure and function in vitro
  • Topoisomerase structure and function in vivo
  • Topoisomerases and antibiotics
  • Topoisomerases and anticancer drugs
  • Topoisomerases and cancer.

Published Papers (5 papers)

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Review

Open AccessReview
Tyrosyl-DNA Phosphodiesterase I N-Terminal Domain Modifications and Interactions Regulate Cellular Function
Genes 2019, 10(11), 897; https://doi.org/10.3390/genes10110897 - 06 Nov 2019
Abstract
The conserved eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1) removes a diverse array of adducts from the end of DNA strand breaks. Tdp1 specifically catalyzes the hydrolysis of phosphodiester linked DNA-adducts. These DNA lesions range from damaged nucleotides to peptide-DNA adducts to [...] Read more.
The conserved eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1) removes a diverse array of adducts from the end of DNA strand breaks. Tdp1 specifically catalyzes the hydrolysis of phosphodiester linked DNA-adducts. These DNA lesions range from damaged nucleotides to peptide-DNA adducts to protein-DNA covalent complexes and are products of endogenously or exogenously induced insults or simply failed reaction products. These adducts include DNA inserted ribonucleotides and non-conventional nucleotides, as well as covalent reaction intermediates of DNA topoisomerases with DNA and a Tdp1-DNA adduct in trans. This implies that Tdp1 plays a role in maintaining genome stability and cellular homeostasis. Dysregulation of Tdp1 protein levels or catalysis shifts the equilibrium to genome instability and is associated with driving human pathologies such as cancer and neurodegeneration. In this review, we highlight the function of the N-terminal domain of Tdp1. This domain is understudied, structurally unresolved, and the least conserved in amino acid sequence and length compared to the rest of the enzyme. However, over time it emerged that the N-terminal domain was post-translationally modified by, among others, phosphorylation, SUMOylation, and Ubiquitinoylation, which regulate Tdp1 protein interactions with other DNA repair associated proteins, cellular localization, and Tdp1 protein stability. Full article
(This article belongs to the Special Issue DNA Topoisomerases in Biology and Medicine)
Open AccessReview
Roles of Topoisomerases in Heterochromatin, Aging, and Diseases
Genes 2019, 10(11), 884; https://doi.org/10.3390/genes10110884 - 01 Nov 2019
Abstract
Heterochromatin is a transcriptionally repressive chromatin architecture that has a low abundance of genes but an enrichment of transposons. Defects in heterochromatin can cause the de-repression of genes and transposons, leading to deleterious physiological changes such as aging, cancer, and neurological disorders. While [...] Read more.
Heterochromatin is a transcriptionally repressive chromatin architecture that has a low abundance of genes but an enrichment of transposons. Defects in heterochromatin can cause the de-repression of genes and transposons, leading to deleterious physiological changes such as aging, cancer, and neurological disorders. While the roles of topoisomerases in many DNA-based processes have been investigated and reviewed, their roles in heterochromatin formation and function are only beginning to be understood. In this review, we discuss recent findings on how topoisomerases can promote heterochromatin organization and impact the transcription of genes and transposons. We will focus on two topoisomerases: Top2α, which catenates and decatenates double-stranded DNA, and Top3β, which can change the topology of not only DNA, but also RNA. Both enzymes are required for normal heterochromatin formation and function, as the inactivation of either protein by genetic mutations or chemical inhibitors can result in defective heterochromatin formation and the de-silencing of transposons. These defects may contribute to the shortened lifespan and neurological disorders observed in individuals carrying mutations of Top3β. We propose that topological stress may be generated in both DNA and RNA during heterochromatin formation and function, which depend on multiple topoisomerases to resolve. Full article
(This article belongs to the Special Issue DNA Topoisomerases in Biology and Medicine)
Open AccessReview
Type II DNA Topoisomerases Cause Spontaneous Double-Strand Breaks in Genomic DNA
Genes 2019, 10(11), 868; https://doi.org/10.3390/genes10110868 - 30 Oct 2019
Abstract
Type II DNA topoisomerase enzymes (TOP2) catalyze topological changes by strand passage reactions. They involve passing one intact double stranded DNA duplex through a transient enzyme-bridged break in another (gated helix) followed by ligation of the break by TOP2. A TOP2 poison, etoposide [...] Read more.
Type II DNA topoisomerase enzymes (TOP2) catalyze topological changes by strand passage reactions. They involve passing one intact double stranded DNA duplex through a transient enzyme-bridged break in another (gated helix) followed by ligation of the break by TOP2. A TOP2 poison, etoposide blocks TOP2 catalysis at the ligation step of the enzyme-bridged break, increasing the number of stable TOP2 cleavage complexes (TOP2ccs). Remarkably, such pathological TOP2ccs are formed during the normal cell cycle as well as in postmitotic cells. Thus, this ‘abortive catalysis’ can be a major source of spontaneously arising DNA double-strand breaks (DSBs). TOP2-mediated DSBs are also formed upon stimulation with physiological concentrations of androgens and estrogens. The frequent occurrence of TOP2-mediated DSBs was previously not appreciated because they are efficiently repaired. This repair is performed in collaboration with BRCA1, BRCA2, MRE11 nuclease, and tyrosyl-DNA phosphodiesterase 2 (TDP2) with nonhomologous end joining (NHEJ) factors. This review first discusses spontaneously arising DSBs caused by the abortive catalysis of TOP2 and then summarizes proteins involved in repairing stalled TOP2ccs and discusses the genotoxicity of the sex hormones. Full article
(This article belongs to the Special Issue DNA Topoisomerases in Biology and Medicine)
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Open AccessReview
Cell Cycle-Dependent Control and Roles of DNA Topoisomerase II
Genes 2019, 10(11), 859; https://doi.org/10.3390/genes10110859 - 30 Oct 2019
Abstract
Type II topoisomerases are ubiquitous enzymes in all branches of life that can alter DNA superhelicity and unlink double-stranded DNA segments during processes such as replication and transcription. In cells, type II topoisomerases are particularly useful for their ability to disentangle newly-replicated sister [...] Read more.
Type II topoisomerases are ubiquitous enzymes in all branches of life that can alter DNA superhelicity and unlink double-stranded DNA segments during processes such as replication and transcription. In cells, type II topoisomerases are particularly useful for their ability to disentangle newly-replicated sister chromosomes. Growing lines of evidence indicate that eukaryotic topoisomerase II (topo II) activity is monitored and regulated throughout the cell cycle. Here, we discuss the various roles of topo II throughout the cell cycle, as well as mechanisms that have been found to govern and/or respond to topo II function and dysfunction. Knowledge of how topo II activity is controlled during cell cycle progression is important for understanding how its misregulation can contribute to genetic instability and how modulatory pathways may be exploited to advance chemotherapeutic development. Full article
(This article belongs to the Special Issue DNA Topoisomerases in Biology and Medicine)
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Open AccessReview
Broken by the Cut: A Journey into the Role of Topoisomerase II in DNA Fragility
Genes 2019, 10(10), 791; https://doi.org/10.3390/genes10100791 - 12 Oct 2019
Abstract
DNA topoisomerase II (TOP2) plays a critical role in many processes such as replication and transcription, where it resolves DNA structures and relieves torsional stress. Recent evidence demonstrated the association of TOP2 with topologically associated domains (TAD) boundaries and CCCTC-binding factor (CTCF) binding [...] Read more.
DNA topoisomerase II (TOP2) plays a critical role in many processes such as replication and transcription, where it resolves DNA structures and relieves torsional stress. Recent evidence demonstrated the association of TOP2 with topologically associated domains (TAD) boundaries and CCCTC-binding factor (CTCF) binding sites. At these sites, TOP2 promotes interactions between enhancers and gene promoters, and relieves torsional stress that accumulates at these physical barriers. Interestingly, in executing its enzymatic function, TOP2 contributes to DNA fragility through re-ligation failure, which results in persistent DNA breaks when unrepaired or illegitimately repaired. Here, we discuss the biological processes for which TOP2 is required and the steps at which it can introduce DNA breaks. We describe the repair processes that follow removal of TOP2 adducts and the resultant broken DNA ends, and present how these processes can contribute to disease-associated mutations. Furthermore, we examine the involvement of TOP2-induced breaks in the formation of oncogenic translocations of leukemia and papillary thyroid cancer, as well as the role of TOP2 and proteins which repair TOP2 adducts in other diseases. The participation of TOP2 in generating persistent DNA breaks and leading to diseases such as cancer, could have an impact on disease treatment and prevention. Full article
(This article belongs to the Special Issue DNA Topoisomerases in Biology and Medicine)
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