Article
Microbiology
Pamela K. Garcia, Rosemarie Martinez Borrero, Thirunavukkarasu Annamalai, Esnel Diaz, Steve Balarezo, Purushottam B. Tiwari, Yuk-Ching Tse-Dinh
Summary: Only about half of the multi-drug resistant tuberculosis (MDR-TB) cases are successfully cured, highlighting the urgent need for new TB treatments. The Mycobacterium tuberculosis (Mtb) topoisomerase I (TopA) has been identified as an essential target for TB drug discovery. Additionally, the toxin MazF4 has been shown to inhibit the topoisomerase I activity. Understanding the mechanism of MazF4's inhibition of Mtb TopA could lead to the discovery of novel inhibitors for the treatment of TB and diseases caused by non-tuberculosis mycobacteria (NTM).
FRONTIERS IN MICROBIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Vita Vidmar, Marlene Vayssieres, Valerie Lamour
Summary: DNA topoisomerases play a crucial role in resolving topological problems in DNA. They can recognize DNA topology and catalyze various reactions by cutting and rejoining DNA. While the mechanisms of DNA cleavage and re-ligation have been extensively studied, the structural rearrangements required for DNA-gate opening and strand transfer, especially in type IA topoisomerases, remain unclear.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Arnaud Vanden Broeck, Christophe Lotz, Robert Drillien, Lea Haas, Claire Bedez, Valerie Lamour
Summary: Human type IIA topoisomerases play a crucial role in regulating DNA topology and chromosome organization. The isoform Topo II alpha is a key target for anti-cancer compounds, forming ternary cleavage complexes with DNA. This study provides cryo-EM structures of the entire Topo II alpha nucleoprotein complex, shedding light on the allosteric connections between different domains and the role of the non-conserved C-terminal domain in regulating enzyme activities.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Brenda Diaz, Christopher Mederos, Kemin Tan, Yuk-Ching Tse-Dinh
Summary: This article mainly introduces the diverse distribution and combinations of two structural elements in the C-terminal regions of type IA topoisomerases, and evaluates their potential structures and DNA-binding mechanisms. The presence of zinc finger structures in fungal species outside of the Ascomycota phylum has been discovered. The highly diverse arrangements and combinations of these regions have important implications for the interactions between microbial topoisomerases and nucleic acids and protein partners.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Microbiology
Uday S. Ganapathy, Ruben Gonzalez Del Rio, Monica Cacho-Izquierdo, Fatima Ortega, Joel Lelievre, David Barros-Aguirre, Wassihun Wedajo Aragaw, Matthew D. Zimmerman, Marissa Lindman, Veronique Dartois, Martin Gengenbacher, Thomas Dick
Summary: Fluoroquinolones are effective against tuberculosis but have limited clinical use for nontuberculous mycobacteria infections due to drug resistance. Researchers tested alternative DNA gyrase inhibitors and found that the MGI EC/11716 not only works against mycobacterium tuberculosis, but also M. abscessus and M. avium. The study showed that EC/11716 is bactericidal against M. abscessus, effective against drug-tolerant biofilms, and successful in a mouse model of M. abscessus lung infection.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Biochemistry & Molecular Biology
Dawei Li, Xiyu Chen, Rumeng Yan, Zeshan Jiang, Bing Zhou, Bei Lv
Summary: It was found that oligodeoxynucleotides (ODNs) containing G-quadruplexes can efficiently inhibit the activity of DNA topoisomerase I. Among them, the parallel propeller-type G-quadruplex is the most effective inhibitor. Combining G-quadruplexes with duplexes to form hybrids can enhance the inhibition efficiency. Moreover, a circular ODN with a G-quadruplex motif and DNA topoisomerase I binding site showed high inhibitory efficiency.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Biochemistry & Molecular Biology
Iris Trindade Jacob, Iranildo Jose da Cruz Filho, Josival Emanuel Ferreira Alves, Felipe de Melo Souza, Rafael David Souto de Azevedo, Diego Santa Clara Marques, Tulio Ricardo Couto de Lima Souza, Keriolaine Lima dos Santos, Maira Galdino da Rocha Pitta, Moacyr Jesus Barreto de Melo Rego, Jamerson Ferreira Oliveira, Sinara Monica Vitalino Almeida, Maria do Carmo Alves de Lima
Summary: This work evaluates the antiproliferative effects and possible mechanisms of indole-thiosemicarbazone compounds LTs with anti-inflammatory activity. The compounds were studied for their binding to HSA, DNA, and human topo, and their fluorescence properties were also analyzed. LT89 exhibited the highest binding constant to HSA, while most compounds showed fluorescent suppression, with LT88 having the highest Stern-Volmer constant. LT76, LT77, and LT87 showed significant antiproliferative effects on DU-145 and Jurkat cells, and LT81 showed the lowest IC50 values on MCF-7 and T-47D cells. Additionally, compounds LT76, LT81, and LT87 inhibited the enzymatic action of human topo II alpha, similar to the positive control amsacrine.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemistry & Molecular Biology
Sabrina X. Van Ravenstein, Kavi P. Mehta, Tamar Kavlashvili, Jo Ann W. Byl, Runxiang Zhao, Neil Osheroff, David Cortez, James M. Dewar
Summary: Using Xenopus egg extracts, this study demonstrates that the TOP2 poisons etoposide and doxorubicin inhibit DNA replication through different mechanisms. Etoposide induces TOP2-dependent DNA breaks and TOP2-dependent fork stalling, while doxorubicin stalls replication forks independently of TOP2 by intercalating into parental DNA.
Article
Multidisciplinary Sciences
Shadi Rabiee, Elham Hoveizi, Mahmood Barati, Ali Salehzadeh, Mohammad Taghi Joghataei, Shima Tavakol
Summary: The cancer microenvironment is crucial in promoting metastasis and malignancy in normal cells. This study investigated the impact of acidic and conditioned media from cancer cells on normal fibroblasts, revealing that acidic media rescued cell survival and altered cell metabolism. The combination of acidic and conditioned media shifted cells towards autophagy rather than apoptosis, and resulted in DNA hypomethylation. Overall, the acidic and conditioned media produced by cancer cells can remotely activate malignant signaling pathways, causing metabolic and epigenetic changes in normal cells.
Article
Biochemistry & Molecular Biology
Paul Villain, Ryan Catchpole, Patrick Forterre, Jacques Oberto, Violette da Cunha, Tamara Basta
Summary: This study reveals the evolutionary history of DNA gyrase in Archaea using phylogenomic approaches and sequence datasets. The results suggest that DNA gyrase was introduced into Euryarchaeal group II through horizontal gene transfer from bacterial ancestors. Furthermore, DNA gyrase has spread to other Archaea lineages through rare horizontal gene transfers. The study also shows the co-evolution of DNA gyrase and Topoisomerase VI in Archaea.
MOLECULAR BIOLOGY AND EVOLUTION
(2022)
Article
Microbiology
Paul Kaminski, Shiyuan Hong, Takeyuki Kono, Paul Hoover, Laimonis Laimins
Summary: Topoisomerases regulate chromatin structures by inducing DNA breaks, with TOP2 beta levels significantly increased in high-risk HPV genomes, contributing to enhanced DNA breaks and blocking HPV replication.
Article
Biochemistry & Molecular Biology
Yu Imai, Glenn Hauk, Jeffrey Quigley, Libang Liang, Sangkeun Son, Meghan Ghiglieri, Michael F. Gates, Madeleine Morrissette, Negar Shahsavari, Samantha Niles, Donna Baldisseri, Chandrashekhar Honrao, Xiaoyu Ma, Jason J. Guo, James M. Berger, Kim Lewis
Summary: The antimicrobial resistance crisis necessitates the development of new antibiotics. In this study, a novel antimicrobial compound called evybactin was discovered from Photorhabdus noenieputensis, which exhibited potent and selective antibacterial activity against Mycobacterium tuberculosis. Evybactin was found to target DNA gyrase and utilized a promiscuous transporter, BacA, to enter the bacterial cell.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Keying Zhu, Yang Wang, Heela Sarlus, Keyi Geng, Erik Nutma, Jingxian Sun, Shin-Yu Kung, Cindy Bay, Jinming Han, Jin-Hong Min, Irene Benito-Cuesta, Harald Lund, Sandra Amor, Jun Wang, Xing-Mei Zhang, Claudia Kutter, Andre Ortlieb Guerreiro-Cacais, Bjorn Hogberg, Robert A. Harris
Summary: This study reveals the promise of TOP1 inhibitors for microglial modulation and highlights the therapeutic strategy of TOP1 inhibition in myeloid cells for neuroinflammatory diseases. The designed nanosystem shows enhanced specificity to myeloid cells and prevents the degradation of the DNA scaffold, offering a potential treatment for diseases with dysfunctional myeloid cells.
Review
Chemistry, Medicinal
Victor M. M. Matias-Barrios, Xuesen Dong
Summary: DNA topoisomerase II (Top2) plays a crucial role in regulating DNA topology by generating temporary breaks, and cancer cells exploit enhanced Top2 functions for transcription and DNA replication during cell division. Inhibitors of Top2 are designed to trap it on DNA, causing cell cycle arrest and cell death. However, resistance to Top2 inhibitors can limit their efficacy, leading to the proposal of combination therapies targeting DNA damage repair machinery and oncogenic pathways for more effective tumor suppression.
Article
Biochemistry & Molecular Biology
Soziema E. E. Dauda, Jessica A. A. Collins, Jo Ann W. Byl, Yanran Lu, Jack C. C. Yalowich, Mark J. J. Mitton-Fry, Neil Osheroff
Summary: Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of antibiotics that target gyrase and topoisomerase IV. NBTIs can induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However, some dioxane-linked amide NBTIs have been found to induce double-stranded DNA breaks mediated by Staphylococcus aureus gyrase. The compound OSUAB-185 induces single-stranded and suppressed double-stranded DNA breaks mediated by Neisseria gonorrhoeae gyrase, while stabilizing both single- and double-stranded DNA breaks mediated by topoisomerase IV.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Microbiology
Marcin J. Szafran, Agnieszka Strzalka, Dagmara Jakimowicz
Article
Microbiology
Malgorzata Plachetka, Dorota Zyla-Uklejewicz, Christoph Weigel, Rafal Donczew, Magdalena Donczew, Dagmara Jakimowicz, Anna Zawilak-Pawlik, Jolanta Zakrzewska-Czerwinska
Review
Microbiology
Monika Pioro, Dagmara Jakimowicz
FRONTIERS IN MICROBIOLOGY
(2020)
Article
Multidisciplinary Sciences
Lukasz Makowski, Damian Trojanowski, Jolanta Zakrzewska-Czerwinska
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
(2020)
Article
Multidisciplinary Sciences
Marta Kolodziej, Damian Trojanowski, Katarzyna Bury, Joanna Holowka, Weronika Matysik, Hanna Kakolewska, Helge Feddersen, Giacomo Giacomelli, Igor Konieczny, Marc Bramkamp, Jolanta Zakrzewska-Czerwinska
Summary: Deletion of the lsr2 gene significantly impacts the cell morphology of M. smegmatis, resulting in cells that are shorter, wider, and more rigid than the wild-type cells.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Aleksandra Kowalczyk, Agata Paneth, Damian Trojanowski, Piotr Paneth, Jolanta Zakrzewska-Czerwinska, Pawel Staczek
Summary: Compounds targeting bacterial topoisomerases have been developed as potential antibacterial agents. Studies have shown that small-molecular weight thiosemicarbazides can act as gyrase and topoisomerase IV inhibitors. These compounds reduce the ATP hydrolysis ability of the ParE subunit of Staphylococcus aureus topoisomerase IV and exhibit better antibacterial activity against clinical strains of S. aureus. Additionally, compound 7 has been shown to prolong the replication process duration in Mycobacterium smegmatis and induce growth arrest of bacterial cells, making it a potential novel group of bacterial topoisomerase inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biotechnology & Applied Microbiology
Martyna Gongerowska-Jac, Marcin Jan Szafran, Dagmara Jakimowicz
Summary: This study introduces a novel approach to identify regulatory proteins that control transcription in Streptomyces. The experimental results demonstrate that the SCO4804 gene positively influences the transcription of topA, revealing a new player in the control of chromosome topology in these bacteria.
MICROBIAL CELL FACTORIES
(2021)
Correction
Multidisciplinary Sciences
Marcin J. Szafran, Tomasz Malecki, Agnieszka Strzalka, Katarzyna Pawlikiewicz, Julia Dulawa, Anna Zarek, Agnieszka Kois-Ostrowska, Kim C. Findlay, Tung B. K. Le, Dagmara Jakimowicz
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Marcin J. Szafran, Tomasz Malecki, Agnieszka Strzalka, Katarzyna Pawlikiewicz, Julia Dulawa, Anna Zarek, Agnieszka Kois-Ostrowska, Kim C. Findlay, Tung B. K. Le, Dagmara Jakimowicz
Summary: Bacteria of the genus Streptomyces have a linear chromosome and undergo substantial rearrangement during sporulation, transitioning from an 'open' to a 'closed' conformation, similar to eukaryotes.
NATURE COMMUNICATIONS
(2021)
Article
Microbiology
Martyna Gongerowska-Jac, Marcin J. Szafran, Jakub Mikolajczyk, Justyna Szymczak, Magdalena Bartynska, Anna Gierlikowska, Sylwia Bialy, Marie A. Elliot, Dagmara Jakimowicz
Summary: The study demonstrates the coordinated gene regulation by global DNA supercoiling and a novel two-component system, SatKR, in Streptomyces bacteria. The regulated genes encode growth and sporulation regulators, showing how these microbes link global regulatory strategies to adjust their life cycle to unfavorable conditions.
Review
Microbiology
Marcin J. Szafran, Dagmara Jakimowicz, Marie A. Elliot
FEMS MICROBIOLOGY REVIEWS
(2020)