Transcriptionally Regulatory Sequences of Phylogenetic Significance
S. K. Dutta in DNA Systematics, 2019
An essential feature of prokaryotic gene regulation lies in timely interaction between the genome and sequence-specific DNA binding proteins. As discussed earlier, initiation and termination involve σ and ρ factor recognition of DNA sequence signals which have been well established. In eukaryotes regulation through protein-DNA interaction is complicated by the structure of their genomes, in which DNA, RNA, and proteins are arranged through subunits such as nucleosomes to form chromatin. Furthermore, while prokaryotic genes may be arranged as operons, many eukaryotic genes may be organized into clusters. If gene clusters are indeed the basic genetic functional units,259 mechanisms regulating the coordinated expression must exist. The organization of chromatin is dynamic; its DNA, RNA, and protein juxtaposition change according to developmental stages or tissue types.
The Scientific Basis of Medicine
John S. Axford, Chris A. O'Callaghan in Medicine for Finals and Beyond, 2023
Every protein is encoded by a DNA sequence within a gene at a defined locus on a chromosome. Codons of three sequential nucleotides encode a single amino acid or a stop signal. Regulatory regions containing target sites for various DNA-binding proteins flank the coding sequence and control gene expression. These regions form a vital part of the gene and their loss can have profound effects on protein expression. Mutations in control regions can cause disease, as evidenced by some of the haemoglobin gene mutations that cause thalassaemia. An upstream promoter provides binding sites for RNA polymerase and transcription factors. Functionally related enhancer sequences are located further afield and recruit various DNA-binding proteins that can regulate the efficiency of gene transcription. The transcriptional unit contains exons of coding DNA separated by introns, which play no part in the finished protein. A large portion of our genome is composed of repetitive DNA of unclear function.
Primary immunodeficiency diseases
Gabriel Virella in Medical Immunology, 2019
Arrested T-cell development due to thymic aplasia or hypoplasia is a hallmark of the syndrome. In some cases, the thymus is absent or reduced in size, as can be noted on ante-posterior and lateral chest X-ray or by computed tomography scan. T cells can be absent (complete DiGeorge syndrome) or reduced in naïve T-cell numbers (partial DiGeorge syndrome). When CD3 counts are less than 500/μL, there can be a poor proliferation response to T-cell mitogens such as phytohemagglutinin (PHA). Children with partial DGS most often have low T-cell numbers for age, elevated CD4 to CD8 T cell ratios, and low numbers of naïve T cells in the blood. The immune deficiency slowly corrects with age, but antibody abnormalities include poor response to immunizations, selective IgA deficiency, hypogammaglobulinemia, and autoimmunity, in the form of autoimmune cytopenias, can persist throughout life. While complete thymic aplasia occurs in only a small percentage of DGS, there are other genetic conditions associated with thymic aplasia. Examples include CHARGE syndrome, associated with mutations in chromo-domain helicase DNA-binding protein-7 (CHD7) gene on chromosome 8q12 or with mutations in the semaphorin-3E gene (SEMA3E; 608166) on chromosome 7q21. Clinical and laboratory manifestations of CHARGE include coloboma of the eyes, heart anomalies, choanal atresia, CNS abnormalities and developmental delay, and genital and ear malformations. The T-cell numbers are absent or very low with deficient function.
Epigenetic modulations in cancer: predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors
Published in Annals of Medicine, 2023
Moustafa M. Madkour, Wafaa S. Ramadan, Ekram Saleh, Raafat El-Awady
DNA methylation is known to affect the interaction with certain DNA-binding proteins including DNA Tops. The role of DNA methylation in controlling the response of cancer cells to drugs including Top I inhibitors was identified by the use of the hypomethylating cytidine analogue 5-azacytidine (5-azaC). The pre-treatment of Chinese hamster ovary cells with 5-azaC was demonstrated to increase their sensitivity to CPT and to result in a strong synergistic effect on chromosomal damage. This could be premised on the idea that changing chromosome replication timing after DNA hypomethylation increases the number of replication forks in early S phase, which subsequently increases the likelihood of collision between a blocked DNA-Top I-CPT cleavage complex and the replication fork [61]. In addition, the cytotoxicity of irinotecan was demonstrated to be increased by 5-azaC in colorectal cancer cells via at least one of the following mechanisms: (a) demethylation of the Top I promoter, (b) indirect stimulation of Top I expression, and (c) amendment of cell cycle progression and/or apoptosis following DNA damage [62,63] (Figure 2(A)). Interestingly, the combination of 5-azaC and irinotecan resulted in a synergistic response with considerable improvement in survival and tumor regression in human colon cancer xenograft mice [64,65]. In pheochromocytoma/paraganglioma, the intermittent coadministration of 5-azaC also increased the efficacy of low doses of CPT and other Top I inhibitors in in vitro and in vivo settings [66].
Immunogenic cell death in a combined synergic gene- and immune-therapy against cancer
Published in OncoImmunology, 2019
Benjamin Nayagom, Ikrame Amara, Meryem Habiballah, Floriane Amrouche, Philippe Beaune, Isabelle de Waziers
HMGB1 is the most abundant non-histone, nuclear protein. It acts as a DNA-binding protein in the nucleus to sustain chromatin structure and it regulates DNA repair. The function of HMGB1 depends upon its localization.28 In the extracellular medium, HMGB1 operates as a potent pro-inflammatory stimulus.29 HMGB1 release was observed when TC1 cells were treated with oxaliplatin (positive control for immunogenic cell death30) and this release was more important when cells were treated with the supernatant of MSC-CYP2B6* treated with CPA. No HMGB1 release was observed in untreated TC1 cells or in TC1 cells incubated with docetaxel or with the supernatant of MSC-NI treated with CPA (Figure 6).
Ternary complex of plasmid DNA with NLS-Mu-Mu protein and cationic niosome for biocompatible and efficient gene delivery: a comparative study with protamine and lipofectamine
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Mohammad Hadi Nematollahi, Masoud Torkzadeh-Mahanai, Abbas Pardakhty, Hossein Ali Ebrahimi Meimand, Gholamreza Asadikaram
EtBr is a universal DNA intercalation dye and its fluorescence intensity increases substantially after binding to DNA. In the presence of another molecule, there would be competition between the new molecule and EtBr for binding to DNA. Such competitive binding studies have been used to identify the new DNA binding protein or drug. Our result confirmed that NMM similar to protamine has the ability to displace EtBr (Figure 4). Therefore, NMM protein is likely to be an intercalator of DNA. Although, the NMM was also able to induce a decrease in EtBr fluorescence but this effect was more obvious in presence of protamine. Similar results regarding protamine EtBr exclusion are also reported by De Ilarduya et al. [39].
Related Knowledge Centers
- Functional Group
- Histone
- Nuclease
- Polymerase
- Protein
- DNA-Binding Domain
- Nucleic Acid Double Helix
- Base Pair
- Transcription Factor
- Regulation of Gene Expression