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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
The two imine moieties (i.e., N10-C11/N10′-C11′) at the top of each seven-membered ring bind covalently to the N2-positions of guanines on opposite DNA strands, thus forming an interstrand cross-link in the minor groove. The molecule spans six DNA base pairs and occupies half a complete turn of the DNA helix. It has a preference for binding to purine-GATC-pyrimidine sequences while recognizing the central GATC sequence. Recognition of the central AT base pairs occurs through hydrogen-bonding interactions between the N3-position of adenine and the N10-proton of the PBD unit on either strand (Figure 5.40). Due to the (S)-stereochemistry at the C11a/C11a′ positions of the molecule, it is perfectly shaped to fit into and follow the contours of the minor groove of DNA with little of the molecule exposed outside of the helix. Unlike other DNA cross-linking agents, this causes virtually no distortion of the DNA helical structure, thus avoiding recognition of the adducts by repair enzymes. In vitro experiments have confirmed this by demonstrating that SJG-136 adducts are repaired very slowly. A. Diagram of the SJG-136/DNA adduct showing the molecule bound to its preferred GATC sequence through an interstrand cross-link between the guanines on opposite strands. The central AT base pairs are recognized by hydrogen bonds between the adenine N3 and PBD N10-H atoms; B. Molecular model showing how SJG-136 fits snugly in the minor groove of DNA with no distortion of the helical structure and little of the molecule exposed beyond the boundaries of the groove.
Bifidobacterium animalis: the missing link for the cancer-preventive effect of Gynostemma pentaphyllum
Published in Gut Microbes, 2021
Weilin Liao, Imran Khan, Guoxin Huang, Shengshuang Chen, Liang Liu, Wai Kit Leong, Xiao Ang Li, Jianlin Wu, W. L. Wendy Hsiao
The data above clearly showed that GpS could stimulate the growth of B. animalis and enhance SCFAs/MCFAs metabolism. We went on to investigate the influence of GpS on gene expressions of B. animalis. The bacteria were inoculated in the growth medium in the presence and absence of GpS. Cells were harvested at a 15-h time point and subjected to RNAseq analysis. As shown in the gene map (Figure 5a and Table S1), 25 genes that were uniquely expressed in the GpS-treated RNA sample. Among the uniquely expressed genes, rpmH, gatC, yajC, ruvA, and rsfS were highly expressed. The network analysis showed that most of these uniquely expressed genes are interconnected through different cellular processes, including RNA processing, α-amino acid biosynthesis and metabolism, anion transmembrane activity, and transferase activity (Figure 5b). Also, lists of GpS-upregulated and downregulated genes are displayed in the heatmaps shown in Figure 5c and listed in Tables S2 and S3. Most of the differentially expressed genes were mapped to various metabolic pathways (Figure 5c).
Autoantibodies in Pandemrix®-induced narcolepsy: Nine candidate autoantigens fail the conformational autoantibody test
Published in Autoimmunity, 2019
Madeleine Wallenius, Alexander Lind, Omar Akel, Emma Karlsson, Markus Svensson, Elin Arvidsson, Anita Ramelius, Carina Törn, Lars Palm, Åke Lernmark, Helena Elding Larsson
The cDNA encoding for candidate autoantigens were obtained (sequences are specified in Supplementary Table 1) and subcloned into the pTNT vector as previously described in detail [20]. DNA sequencing was verified by GATC (GATC Biotech AG, Konstanz, Germany) and Thermo Fisher Scientific (Carlsbad, CA). Radio-labelled proteins were expressed through coupled in vitro transcription translation by mixing cDNA with the TnT® SP6 Coupled Reticulocyte Lysate System, as described by the manufacturer (Promega, Madison, WI), and 35S-methionine (PerkinElmer Life and Analytical Sciences, Brussels, Belgium). Unincorporated 35S-methionine was removed following incubation (90 min at 30 °C) using a Nap5 column (GE Healthcare Bio-Sciences, Uppsala, Sweden). The mean incorporation rate of radio-labelled proteins were ppHypocretin 19%, HCRTR2 16%, TRIB2 10%, α-MSH/POMC 17%, DP1 47%, KIR4.1 25% and ANO2 39%.
Effects of dam and seqA genes on biofilm and pellicle formation in Salmonella
Published in Pathogens and Global Health, 2018
Sinem Uğur, Nefise Akçelik, Fatma Neslihan Yüksel, Neslihan Taşkale Karatuğ, Mustafa Akçelik
The Dam adenine methyltransferase enzyme encoded by the dam gene recognizes the GATC sequences on the double-stranded DNA and is methylated at position N6. This hemimethylated state of the newly synthesized DNA: allows time for the repair of incorrectly matched bases, the regulation of gene expression, the suppression of the onset of chromosomal replication, and the activation or suppression of cell cycle-related processes [36]. The SeqA protein requires at least two hemimethylated GATC sequences on the same side of the DNA to demonstrate high binding activity. Here it is determined that the SeqA protein function as a nucleoid organizing protein [36]. Proteins involved in the formation and maintenance of chromosome structure, such as SeqA protein, are known to function as global regulators [37].