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
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
Multidisciplinary Sciences
Elizabeth G. Gibson, Joseph E. Deweese
Summary: In this study, the mechanism of etoposide resistance caused by specific mutations in TOP2A is investigated using biochemical and structural data. The findings suggest that mutations can impact the symmetrical relationships in the active site and surrounding regions, which in turn affect the coordination of DNA cleavage. The results highlight the importance of both local and long-distance factors in etoposide action, indicating interdependent relationships between structure and function.
Article
Biochemistry & Molecular Biology
Hannah E. Carter, Baylee Wildman, Heidi A. Schwanz, Robert J. Kerns, Katie J. Aldred
Summary: Fluoroquinolones, an important class of antibacterials, are facing a threat to their clinical efficacy due to rising levels of resistance. Understanding the mechanism of action of these drugs against target enzymes could help in designing more effective quinolone-based drugs to overcome resistance. This study investigates the existence and function of the water-metal ion bridge in the Gram-negative gyrase, which has been found in other type II topoisomerases. Evidence suggests that this bridge does exist in quinolone interactions with the gyrase enzyme and plays a positioning role. Further studies will explore the universality of this bridge and its implications.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Keishi Shintomi, Tatsuya Hirano
Summary: Topoisomerase II alpha plays a crucial role in mitotic chromatid assembly. By refining the mitotic chromatid reconstitution assay, researchers have gained new insights into the C-terminal domain (CTD) of topo II alpha. The CTD contributes to proper formation of nucleosome-depleted chromatids and fine-tunes the enzymatic core delivery process during mitotic chromatid assembly.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Priti Thakur, Jowad Atway, Patrick A. Limbach, Balasubrahmanyam Addepalli
Summary: Knowledge of the cleavage specificity of ribonucleases is critical for their application in RNA modification mapping or RNA-protein binding studies. In this study, the cleavage specificity and efficiency of ribonuclease MC1 and cusativin were investigated using a customized RNA sequence. The results showed that both enzymes exhibited different preferences for dinucleotide combinations, and the observed substrate specificity was supported by molecular docking analysis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Matej Janezic, Katja Valjavec, Kaja Bergant Loboda, Barbara Herlah, Iza Ogris, Mirijam Kozorog, Marjetka Podobnik, Simona Golic Grdadolnik, Gerhard Wolber, Andrej Perdih
Summary: In this study, human DNA topoisomerase II alpha was utilized as a model target and a dynophore-based approach was used to design catalytic inhibitors. Through virtual screening of a library of natural compounds, flavonoid compounds with promising topoisomerase II alpha catalytic inhibition were identified. The study not only demonstrates a new design strategy that incorporates a dynamic component of molecular recognition but also highlights new derivates in the established flavonoid class of topoisomerase II inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Martin Bartas, Kristyna Slychko, Jiri Cerven, Petr Pecinka, Donna J. Arndt-Jovin, Thomas M. Jovin
Summary: Dynamic processes in genomic DNA lead to topological challenges, which are resolved by DNA topoisomerases. A highly-conserved protein, TopoII, has been found to have a strong affinity for Z-DNA and may play a structural role in recognizing Z-DNA segments.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
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)
Article
Biochemistry & Molecular Biology
Honghai Tang, Hui Yuan, Wenhao Du, Gan Li, Dongmei Xue, Qiang Huang
Summary: CRISPR-Cas9 is a powerful tool for precise genome editing in living cells, and modeling techniques have been used to understand the atomic structures and mechanisms involved in DNA cleavage by the system. The presented atomic model of the SpCas9-sgRNA-DNA complex in the cleavage state provides insights into the active sites and interactions involved in DNA cleavage. Further, the engineered SpCas9 variant with reduced off-target effects showcases the potential for improved specificity in CRISPR-Cas9 editing systems.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Review
Geriatrics & Gerontology
Morgan Crewe, Ram Madabhushi
Summary: The nervous system is susceptible to genomic instability and mutations in DNA damage response factors can lead to neurological disorders. The main sources and mechanisms of DNA damage relevant to neuronal dysfunction are not well understood. Topoisomerase-mediated DNA damage may be a significant underlying source of neuronal dysfunction.
FRONTIERS IN AGING NEUROSCIENCE
(2021)
Article
Multidisciplinary Sciences
Heyjin Son, Jaeil Park, Injoo Hwang, Youngri Jung, Sangsu Bae, Sanghwa Lee
Summary: In the study, two conformational intermediates were identified in the process of Cas12a cleaving double-stranded DNA target, including PAM-distal DNA unwound conformation and the binding of the target strand to the catalytic site. These findings highlighted the importance of Mg2+ ions in promoting the binding and cleavage of the target strand, and proposed a Mg2+-dependent kinetic model for the mechanism of Cas12a achieving cleavage of the target DNA.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Zehra Kubra Yilmaz, Ozlem Ozdemir, Belma Aslim, Zekiye Suludere, Egemen Sahin
Summary: In this study, a newly synthesized asymmetric-Schiff base was investigated for its interaction with DNA and its antiproliferative activity against tumor cells. The compound was found to effectively bind to DNA and exhibited a concentration- and time-dependent decrease in cell viability. It also induced DNA damage in tumor cells and showed potential as a DNA-targeting antitumor drug.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemical Research Methods
Majid Arvand, Hoda Ilkhani, Mohamad Reza Ganjali, Akram Pourhabib
Summary: A new Tb complex Tb(QS)3 was used to investigate the interaction between the complex and double-stranded DNA, leading to the design of a new DNA biosensor. The interaction mechanism, primarily intercalative interaction, was elucidated using electrochemical methods such as cyclic voltammetry and differential pulse voltammetry.
ANALYTICAL BIOCHEMISTRY
(2022)
Article
Chemistry, Medicinal
Ilija N. Cvijetic, Barbara Herlah, Aleksandar Marinkovic, Andrej Perdih, Snezana K. Bjelogrlic
Summary: Phenotypic screening identified 1,5-bis(salicylidene)thiocarbohydrazide as a promising compound against leukemia and breast cancer cells, inhibiting DNA replication through a ROS-independent pathway. The similarity of thiocarbohydrazone to known thiosemicarbazone inhibitors targeting DNA topoisomerase IIa prompted investigation of their inhibition activity. Computational assessment provided insights for further optimization of this lead compound for anticancer drug development.
Article
Chemistry, Medicinal
James T. Wilson, Xiaohua Jiang, Bradley C. McGill, Edward C. Lisic, Joseph E. Deweese
CHEMICAL RESEARCH IN TOXICOLOGY
(2016)
Article
Chemistry, Medicinal
Elizabeth G. Gibson, McKenzie M. King, Susan L. Mercer, Joseph. E. Deweese
CHEMICAL RESEARCH IN TOXICOLOGY
(2016)
Article
Chemistry, Medicinal
James T. Wilson, Cole A. Fief, Klarissa D. Jackson, Susan L. Mercer, Joseph E. Deweese
CHEMICAL RESEARCH IN TOXICOLOGY
(2018)
Article
Biochemistry & Molecular Biology
Nicholas A. Smith, Jo Ann W. Byl, Susan L. Mercer, Joseph E. Deweese, Neil Osheroff
Article
Biochemistry & Molecular Biology
R. Hunter Lindsey, MaryJean Pendleton, Rachel E. Ashley, Susan L. Mercer, Joseph E. Deweese, Neil Osheroff
Article
Chemistry, Medicinal
Kellie M. Regal, Susan L. Mercer, Joseph E. Deweese
CHEMICAL RESEARCH IN TOXICOLOGY
(2014)
Article
Chemistry, Medicinal
William H. Morris, Lana Ngo, James T. Wilson, Wathsala Medawala, Anthony R. Brown, Jennifer D. Conner, Florence Fabunmi, Derek J. Cashman, Edward C. Lisic, Tao Yu, Joseph E. Deweese, Xiaohua Jiang
CHEMICAL RESEARCH IN TOXICOLOGY
(2019)
Article
Chemistry, Medicinal
J. Myles Keck, Jennifer D. Conner, James T. Wilson, Xiaohua Jiang, Edward C. Lisic, Joseph E. Deweese
CHEMICAL RESEARCH IN TOXICOLOGY
(2019)
Article
Chemistry, Multidisciplinary
Ashley C. Dougherty, Mariam G. Hawaz, Kristine G. Hoang, Judy Trac, Jacob M. Keck, Carmen Ayes, Joseph E. Deweese
Summary: TOP2A is an essential nuclear enzyme for resolving DNA knots during replication and cell division. Mutations in the C-terminal domain of TOP2A can affect catalytic activity and substrate interaction. Targeting specific positions in the C-terminal domain may provide a way to regulate the enzyme, with certain mutants showing increased DNA cleavage levels in the presence of etoposide compared to wild-type TOP2A.
Article
Religion
Joseph E. Deweese, Debb Wilcox, Thomas C. Campbell, Jeff McCormack, Catherine L. Terry, Roger L. Davis
Summary: Faith, values, and ethics are crucial for all individuals to learn, especially for healthcare providers. This course developed at a private Christian college of pharmacy used a longitudinal approach with three interconnected themes to explore how faith and professional practice merge. Engaging students through guest presenters, panel discussions, interactive interviews, and small group discussions, the course serves as a model for discussing faith, values, and ethics in healthcare education.
INTERNATIONAL JOURNAL OF CHRISTIANITY & EDUCATION
(2022)
Review
Biochemistry & Molecular Biology
Xiaohua Jiang, Lauren A. A. Fielding, Hunter Davis, William Carroll, Edward C. C. Lisic, Joseph E. E. Deweese
Summary: Topoisomerases, crucial enzymes for DNA metabolism, have been targeted by anti-cancer therapeutics, including thiosemicarbazones (TSC) and metal-TSC complexes. TSCs and metal-chelated TSCs exhibit potential anti-cancer effects by inhibiting various human topoisomerases, particularly topoisomerase II. The mechanisms by which these compounds inhibit topoisomerases are still under investigation. This review summarizes the inhibition of different human topoisomerases by TSCs and metal-TSCs, highlighting the unanswered questions about these diverse compounds.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Judy Trac, J. Myles Keck, Joseph E. Deweese
Summary: Cannabidiol and related cannabinoids, such as the cannabinoid-quinone HU-331, are being explored for their potential as anticancer therapeutics. Studies have shown that HU-331 displays anticancer activity without the adverse effects associated with traditional anticancer agents. In animal models, HU-331 has demonstrated the ability to shrink tumors without causing cardiotoxicity, supporting further research into its potential for cancer treatment.
JOURNAL OF CANNABIS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Matthew B. Murphy, Priyanka Kumar, Amber M. Bradley, Christopher E. Barton, Joseph E. Deweese, Susan L. Mercer
BIOORGANIC & MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Multidisciplinary
Cole A. Fief, Kristine G. Hoang, Stephen D. Phipps, Jessica L. Wallace, Joseph E. Deweese
Article
Education & Educational Research
Adam C. Pace, Joy Greene, Joseph E. Deweese, Dana A. Brown, Ginger Cameron, James M. Nesbit, Terri Wensel
CHRISTIAN HIGHER EDUCATION
(2017)