1,721,050 research outputs found
Development of DNA topoisomerase-related therapeutics: a short perspective of new challenges.
No full textAntitumor agents targeting DNA and DNA-assocd. processes are widely used in the treatment of human cancers and produce significant increases in the survival of patients. DNA topoisomerases remain the most significant target of these cytotoxic drugs and constitute a growing family of nuclear enzymes that regulate DNA topol. during DNA replication and recombination, DNA transcription, chromosome condensation-decondensation and segregation. Major progress has been attained in recent years in the understanding of the structures of these enzymes and their main cellular functions, hopefully providing new opportunities for pharmacol. interventions. New leads and derivs. of known structures have been reported recently, and here they will be discussed highlighting the challenges to find innovative and more effective drugs. Moreover, we will review novel and diverse approaches relevant to the development of new topoisomerase-related therapeutics
Drugs acting on DNA topoisomerases: Recent advances and future perspectives
No full textDNA-topoisomerases, a family of DNA-processing enzymes, represent the pharmacological target of major clinically useful chemotherapeutic agents. These drugs essentially act by trapping a topoisomerase-DNA cleavable complex, an intermediate in the enzyme s catalytic cycle. Research activity in this field continues to grow exponentially, resulting in a wealth of new information on the functional role and the biochemical and structural properties of the enzymes. In addition, the drug pharmacophores have been further characterized, along with their sequence preferences, and key interactions with the target macromolecules are being unveiled. This review will discuss the recent advances in elucidating the mode of action of DNA-topoisomerases and of topoisomerase-targeted anticancer agents
Unique sequence specificity of topoisomerase II DNA cleavage stimulation and DNA binding mode of streptonigrin
No full textG-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells
Full text linkG-quadruplexes (G4s) are non-canonical nucleic acid structures involved in fundamental biological processes. As G4s are promising anticancer targets, in past decades the search for effective anticancer G4 binders aimed at the discovery of more cytotoxic ligands interfering with specific G4 structures at oncogenes or telomeres. Here, we have instead observed a significant activation of innate immune genes by two unrelated ligands at non-cytotoxic concentrations. The studied G4 binders (pyridostatin and PhenDC3) can induce an increase of micronuclei triggering the activation of the cytoplasmic STING (stimulator of interferon response cGAMP interactor 1) signaling pathway in human and murine cancer cells. Ligand activity can then lead to type I interferon production and innate immune gene activation. Moreover, specific gene expression patterns mediated by a G4 binder in cancer cells correlate with immunological hot features and better survival in human TCGA (The Cancer Genome Atlas) breast tumors. The findings open to the development of cytostatic G4 binders as effective immunomodulators for combination immunotherapies in unresponsive tumors
Non-B DNA structures as a booster of genome instability
Full text linkNon-canonical secondary structures (NCSs) are alternative nucleic acid structures that differ from the canonical B-DNA conformation. NCSs often occur in repetitive DNA sequences and can adopt different conformations depending on the sequence. The majority of these structures form in the context of physiological processes, such as transcription-associated R-loops, G4s, as well as hairpins and slipped-strand DNA, whose formation can be dependent on DNA replication. It is therefore not surprising that NCSs play important roles in the regulation of key biological processes. In the last years, increasing published data have supported their biological role thanks to genome-wide studies and the development of bioinformatic prediction tools. Data have also highlighted the pathological role of these secondary structures. Indeed, the alteration or stabilization of NCSs can cause the impairment of transcription and DNA replication, modification in chromatin structure and DNA damage. These events lead to a wide range of recombination events, deletions, mutations and chromosomal aberrations, well-known hallmarks of genome instability which are strongly associated with human diseases. In this review, we summarize molecular processes through which NCSs trigger genome instability, with a focus on G-quadruplex, i-motif, R-loop, Z-DNA, hairpin, cruciform and multi-stranded structures known as triplexes. (c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
The topoisomerase II poison clerocidin alkylates non-paired guanines of DNA: implications for the irreversible stimulation of DNA cleavage
Full text linkClerocidin, a diterpenoid with antibacterial and antitumor activity, stimulates in vitro DNA cleavage mediated by mammalian and bacterial topoisomerase (topo) II. Different from the classical topoisomerase poisons, clerocidin-stimulated breaks at guanines immediately preceding the sites of DNA cleavage are not resealed upon heat or salt treatment. To understand the mechanism of irreversible trapping of the topo II-cleavable complex, we have investigated the reactivity of clerocidin per se towards DNA. We show here that the drug is able to nick negatively supercoiled plasmids. DNA cleavage by clerocidin in enzyme-free medium is due to the ability of the drug to form covalent adducts with guanines. Indeed, clerocidin was able to specifically react with short oligonucleotides when the guanines were unpaired and exposed as in bulges or in the single-strand form. The clerocidin epoxy group attacks the nitrogen at position 7 of guanines, leading to strand scission at the modified site. Our findings also demonstrate that trapping of topoisomerases by clerocidin is specific for type II enzymes. The guanine-alkylating ability of clerocidin suggests an unprecedented mechanism of topo II poisoning, according to which the enzyme renders the drug reactive toward DNA by distorting the double-helical structure of the nucleic acid at the cleavage site
Ligands stimulating antitumour immunity as the next G-quadruplex challenge
Full text linkG-quadruplex (G4) binders have been investigated to discover new anticancer drugs worldwide in past decades. As these ligands are generally not highly cytotoxic, the discovery rational was mainly based on increasing the cell-killing potency. Nevertheless, no G4 binder has been shown yet to be effective in cancer patients. Here, G4 binder activity at low dosages will be discussed as a critical feature to discover ligands with therapeutic effects in cancer patients. Specific effects of G4 binders al low doses have been reported to occur in cancer and normal cells. Among them, genome instability and the stimulation of cytoplasmic processes related to autophagy and innate immune response open to the use of G4 binders as immune-stimulating agents. Thus, we propose a new rational of drug discovery, which is not based on cytotoxic potency but rather on immune gene activation at non-cytotoxic dosage
Antisense transcripts enhanced by camptothecin at divergent CpG-island promoters associated with bursts of topoisomerase I-DNA cleavage complex and R-loop formation
No full textDNA Topoisomerase I (Top1) is required to relax DNA supercoils generated by RNA polymerases (RNAPs). Top1 is inhibited with high specificity by camptothecin (CPT), an effective anticancer agent, and by oxidative base damage and ribonucleotides in DNA strands, resulting into Top1-DNA cleavage complexes (Top1ccs). To understand how Top1ccs affect genome stability, we have investigated the global transcriptional response to CPT-induced Top1ccs. Top1ccs trigger an accumulation of antisense RNAPII transcripts specifically at active divergent CpG-island promoters in a replication-independent and Top1-dependent manner. As CPT increases antisense transcript levels in the presence of 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, a transcription inhibitor, Top1ccs likely impair antisense RNA degradation. Time-course data showed a burst of Top1ccs increased by CPT at promoter sites and along transcribed regions, causing a transient block of RNAPII at the promoter. Moreover, cell immunofluorescence analyses showed that Top1ccs induce a transient increase of R-loops specifically at highly transcribed regions such as nucleoli in a Top1-dependent manner. Thus, a specific and highly dynamic transcriptional response to Top1ccs occurs at divergent active CpG-island promoters, which may include a transient stabilization of R-loops. The results clarify molecular features of a response pathway leading to transcription-dependent genome instability and altered transcription regulation
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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