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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Topoisomerase I (Topo I) is an essential DNA topology-controlling enzyme that works by transiently breaking one strand of a DNA duplex and passing the second strand through the break followed by re-sealing, thus preventing the relief of supercoiling resulting from DNA unwinding. This is an absolute requirement for many nuclear processes, including replication, transcription, and recombination. As some cancer cells grow and reproduce at a faster rate than normal cells, they may be more vulnerable to topoisomerase I inhibition, which is one possible explanation for their selective toxicity of these agents. An alternative explanation is that some tumor cells may be deficient in the repair pathways necessary to deal with the single-strand nicks, thus making them more vulnerable.
Fetal Growth Factors*
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
Philip A. Gruppuso, Thomas R. Curran, Roderick I. Bahner
Evidence for involvement of phosphorylation cascades in EGF action has come from studies showing EGF activation of serine/threonine kinases,59 including casein kinase II, raf, and the mitogen activated protein (MAP) kinase. The substrates for these kinases are diverse. They include transcription factors, enzymes which modify DNA topology, cytostructural proteins, and regulators of protein synthesis. In a number of cases kinase activation is coupled to downstream activation of yet another kinase. Importantly, such cascades provide for signal amplification at each phosphorylation step.
Role of Sperm DNA Damage in Male Infertility Assessment
Published in Botros Rizk, Ashok Agarwal, Edmund S. Sabanegh, Male Infertility in Reproductive Medicine, 2019
Saradha Baskaran, Chak-Lam Cho, Ashok Agarwal
During spermiogenesis, the paternal genome undergoes precise packaging that imparts a unique architecture and compactness to the nucleus, which is crucial for fertilization and embryogenesis [4]. McPherson and Longo [21,22] proposed the indispensable role of endogenous nuclease, topoisomerase II, in chromatin packing. It is primarily involved in creating and ligating nicks that facilitates protamination. This drastic change in DNA topology provides relief of torsional stress and aids chromatin reorganization during the dislodgment of histones by protamines [4,21]. Topoisomerase II changes DNA topology by inducing double-strand break and its subsequent religation [23]. The unresolved strand breaks due to failure in the religation process by topoisomerase II can have adverse consequences on the genomic integrity of male gamete. Endogenous nicks in DNA are evident during the transition from round to elongated spermatids in the testis but not detected once the chromatin packing is complete [21,22]. Therefore, the presence of endogenous strand breaks in ejaculated spermatozoa signifies incomplete maturation during spermiogenesis.
Bacterial death from treatment with fluoroquinolones and other lethal stressors
Published in Expert Review of Anti-infective Therapy, 2021
Many bacterial species contain two type-II DNA topoisomerases, DNA gyrase and DNA topoisomerase IV (some, such as Mycobacterium tuberculosis, contain only gyrase). These enzymes alter DNA topology by introducing a double-strand break, passing another duplex (or a another region of the same duplex) through the break, and then resealing the break. The quinolones form complexes with either gyrase or topoisomerase IV and DNA that is broken such that each 5ʹ end is covalently bound to either GyrA (gyrase) or ParC (topoisomerase IV) [15,16]. Since the DNA is broken, the complex is called a cleaved complex (Figure 3). The presence of a covalent protein-DNA link allows the DNA break to readily reseal when quinolone is removed. As expected, cleaved-complex formation in vitro is reversible [17,18].
Irinotecan hydrochloride trihydrate loaded folic acid-tailored solid lipid nanoparticles for targeting colorectal cancer: development, characterization, and in vitro cytotoxicity study using HT-29 cells
Published in Journal of Microencapsulation, 2019
Kuldeep Rajpoot, Sunil K. Jain
Irinotecan hydrochloride trihydrate (IHT), a water-soluble semisynthetic derivative of camptothecin, frequently used in the management of CRC and malignancies related to small cells in the lung (Bansal et al.2008, Maltas et al.2013). IHT is identified to interact precisely with the topoisomerase that regulates DNA topology and accomplish various nuclear processes, viz., DNA replication, recombination, and repair. IHT binds to the topoisomerase I and stop the replication of DNA (de Jong et al.2006). Current research reported that IHT is responsible for damage of double-strand of DNA during the interaction of replicating enzymes with ternary complex produced using DNA, topoisomerase I, and IHT. Thus, IHT prevents the synthesis of new DNA molecules needed for the mammalian cells by inhibiting the repairing of double-strand breaks in DNA (Charasson et al.2002). While in transcription, the IHT inactivates enzyme (forming a covalent complex, i.e. DNA and topoisomerase-I enzyme) to hinder RNA formation. Cytotoxicity of the IHT drug for S-phase is specific in the cell cycle (Morland et al.2014). In the case of CRC, the DNA replication in a tumour cell can be inhibited via the use of IHT (Tamyurek et al.2015).
DNA topoisomerases as molecular targets for anticancer drugs
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Kamila Buzun, Anna Bielawska, Krzysztof Bielawski, Agnieszka Gornowicz
DNA topoisomerases are a group of enzymes that control DNA topology. They are involved in many significant biological processes in all cells (e.g. DNA replication, transcription and recombination or chromosome condensation)6. These enzymes bind covalently to the DNA phosphorus group, split the DNA strand or strands and finally reunite them. According to their mechanism of action, there are two main types of topoisomerases: topoisomerases I (Top I) and topoisomerases II (Top II) divided into five subfamilies (see Table 1).