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Advances in Structure, Function and Molecular Targeting of DNA Topoisomerases: 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 10 February 2025 | Viewed by 4214

Special Issue Editors

Prof. Dr. Joseph E. Deweese

E-Mail Website
Guest Editor
1. Professor of Biochemistry, Freed-Hardeman University, Henderson, TN 38340, USA
2. Adjunct Associate Professor, Biochemistry Department, Vanderbilt University, Nashville, TN 37232, USA
Interests: DNA topoisomerases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Neil Osheroff

E-Mail Website
Guest Editor
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Interests: topoisomerase
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Topoisomerases are essential enzymes in living systems that play critical roles in transcription, replication, cell division, and DNA damage repair. Over the last 45+ years, many facets of the function of these enzymes have been elucidated, but critical questions remain. Although attempts to answer some fundamental questions of functions and mechanisms have been made, additional questions related to regulation, localization, and protein–protein interactions have been raised. Further, the utility of anticancer and antibacterial drugs targeting topoisomerases has been widely recognized, and many chemotherapeutic regimens still include topoisomerase poisons. Thus, we must continue to explore both the available agents and new ones.

This Special Issue of the International Journal of Molecular Sciences focuses on topoisomerases and welcomes both original research articles and review papers that deal with advances in our understanding of topoisomerase structures, functions, and molecular targeting for therapeutic purposes.

Prof. Dr. Joseph E. Deweese
Prof. Dr. Neil Osheroff
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • topoisomerase
  • DNA supercoiling
  • DNA topology
  • anticancer
  • antimicrobial
  • DNA damage

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Published Papers (3 papers)

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Research

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11 pages, 7411 KiB  
Article
Small Molecule Inhibitors of Mycobacterium tuberculosis Topoisomerase I Identified by Machine Learning and In Vitro Assays
by Somaia Haque Chadni, Matthew A. Young, Pedro Igorra, Md Anisur Rahman Bhuiyan, Victor Kenyon and Yuk-Ching Tse-Dinh
Int. J. Mol. Sci. 2024, 25(22), 12265; https://doi.org/10.3390/ijms252212265 - 15 Nov 2024
Viewed by 900
Abstract
Tuberculosis (TB) caused by Mycobacterium tuberculosis is a leading infectious cause of death globally. The treatment of patients becomes much more difficult for the increasingly common multi-drug resistant TB. Topoisomerase I is essential for the viability of M. tuberculosis and has been validated [...] Read more.
Tuberculosis (TB) caused by Mycobacterium tuberculosis is a leading infectious cause of death globally. The treatment of patients becomes much more difficult for the increasingly common multi-drug resistant TB. Topoisomerase I is essential for the viability of M. tuberculosis and has been validated as a new target for the discovery of novel treatment against TB resistant to the currently available drugs. Virtual high-throughput screening based on machine learning was used in this study to identify small molecules that target the binding site of divalent ion near the catalytic tyrosine of M. tuberculosis topoisomerase I. From the virtual screening of more than 2 million commercially available compounds, 96 compounds were selected for testing in topoisomerase I relaxation activity assay. The top hit that has IC50 of 7 µM was further investigated. Commercially available analogs of the top hit were purchased and tested with the in vitro enzyme assay to gain further insights into the molecular scaffold required for topoisomerase inhibition. Results from this project demonstrated that novel small molecule inhibitors of bacterial topoisomerase I can be identified starting with the machine-learning-based virtual screening approach. Full article
(This article belongs to the Special Issue Advances in Structure, Function and Molecular Targeting of DNA Topoisomerases: 2nd Edition)
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19 pages, 4292 KiB  
Article
Bioinformatic Analysis of Topoisomerase IIα Reveals Interdomain Interdependencies and Critical C-Terminal Domain Residues
by Clark E. Endsley, Kori A. Moore, Thomas D. Townsley, Kirk K. Durston and Joseph E. Deweese
Int. J. Mol. Sci. 2024, 25(11), 5674; https://doi.org/10.3390/ijms25115674 - 23 May 2024
Viewed by 1681
Abstract
DNA Topoisomerase IIα (Top2A) is a nuclear enzyme that is a cancer drug target, and there is interest in identifying novel sites on the enzyme to inhibit cancer cells more selectively and to reduce off-target toxicity. The C-terminal domain (CTD) is one potential [...] Read more.
DNA Topoisomerase IIα (Top2A) is a nuclear enzyme that is a cancer drug target, and there is interest in identifying novel sites on the enzyme to inhibit cancer cells more selectively and to reduce off-target toxicity. The C-terminal domain (CTD) is one potential target, but it is an intrinsically disordered domain, which prevents structural analysis. Therefore, we set out to analyze the sequence of Top2A from 105 species using bioinformatic analysis, including the PSICalc algorithm, Shannon entropy analysis, and other approaches. Our results demonstrate that large (10th-order) interdependent clusters are found including non-proximal positions across the major domains of Top2A. Further, CTD-specific clusters of the third, fourth, and fifth order, including positions that had been previously analyzed via mutation and biochemical assays, were identified. Some of these clusters coincided with positions that, when mutated, either increased or decreased relaxation activity. Finally, sites of low Shannon entropy (i.e., low variation in amino acids at a given site) were identified and mapped as key positions in the CTD. Included in the low-entropy sites are phosphorylation sites and charged positions. Together, these results help to build a clearer picture of the critical positions in the CTD and provide potential sites/regions for further analysis. Full article
(This article belongs to the Special Issue Advances in Structure, Function and Molecular Targeting of DNA Topoisomerases: 2nd Edition)
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Review

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16 pages, 1096 KiB  
Review
Genome Instability Induced by Topoisomerase Misfunction
by Karin C. Nitiss, Afif Bandak, James M. Berger and John L. Nitiss
Int. J. Mol. Sci. 2024, 25(19), 10247; https://doi.org/10.3390/ijms251910247 - 24 Sep 2024
Viewed by 974
Abstract
Topoisomerases alter DNA topology by making transient DNA strand breaks (DSBs) in DNA. The DNA cleavage reaction mechanism includes the formation of a reversible protein/DNA complex that allows rapid resealing of the transient break. This mechanism allows changes in DNA topology with minimal [...] Read more.
Topoisomerases alter DNA topology by making transient DNA strand breaks (DSBs) in DNA. The DNA cleavage reaction mechanism includes the formation of a reversible protein/DNA complex that allows rapid resealing of the transient break. This mechanism allows changes in DNA topology with minimal risks of persistent DNA damage. Nonetheless, small molecules, alternate DNA structures, or mutations in topoisomerase proteins can impede the resealing of the transient breaks, leading to genome instability and potentially cell death. The consequences of high levels of enzyme/DNA adducts differ for type I and type II topoisomerases. Top1 action on DNA containing ribonucleotides leads to 2–5 nucleotide deletions in repeated sequences, while mutant Top1 enzymes can generate large deletions. By contrast, small molecules that target Top2, or mutant Top2 enzymes with elevated levels of cleavage lead to small de novo duplications. Both Top1 and Top2 have the potential to generate large rearrangements and translocations. Thus, genome instability due to topoisomerase mis-function is a potential pathogenic mechanism especially leading to oncogenic progression. Recent studies support the potential roles of topoisomerases in genetic changes in cancer cells, highlighting the need to understand how cells limit genome instability induced by topoisomerases. This review highlights recent studies that bear on these questions. Full article
(This article belongs to the Special Issue Advances in Structure, Function and Molecular Targeting of DNA Topoisomerases: 2nd Edition)
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