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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
Usually 25 bases in length, Morpholinos bind to complementary sequences of RNA by standard nucleic acid base pairing. They do not degrade their target RNA molecules, unlike many antisense structural types (e.g., phosphorothioates, siRNA). Instead, they act by binding to a target RNA sequence and causing a steric block to transcription. In particular, bound to the 5′-untranslated region of messenger RNA (mRNA), they can interfere with the progression of the ribosomal initiation complex from the 5′-cap to the start codon. This prevents translation of the coding region of the targeted transcript.
The Acute Phase Complement Proteins
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Volanakis and colleagues50 suggest that translational control of C2 is due to differences in transcriptional initiation. These generate differences in the 5′ untranslated region, the sequence of which governs the rate of C2 translation. Further analysis of this interesting finding in the context of tissue specificity of C2 expression is warranted.
Homocystinuria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The locus for human cystathionine β-synthase was mapped to chromosome 21 in Chinese hamster-human cell hybrids [39], and cDNA prepared from immunopurified mRNA was used to verify the locus at the subtelomeric region of chromosome 21q22.3 [40], where it is syntenic with α−A-crystallin. There are 23 exons over some 28 kb [41], from which the 551 amino acids are encoded by exons 1–14 and 16. Alternate splicing may include exon 15, which is represented in a few mRNA molecules, but its 14 encoded amino acids are not found in the expressed enzyme. There is also alternative splicing among five exons (designated −1a to −1e) in the 5′-untranslated region. More than 170 mutations have been identified [42], and the functional consequences in many have been confirmed by expression systems. Among the first to be identified was a G to A change at 919 in exon 8, which converts glycine 307 to serine [43], and this mutation is the leading cause of homocystinuria in Ireland. This, and the pyridoxine-responsive I278T, were the most common of 310 homocystinuric alleles [44].
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
As the name implies, cell-based RNA-small molecule screening systems are conducted within various cell lines. These systems have been used to identify small molecules capable of inhibiting the activity of noncoding RNAs such as miRNAs, translation by targeting 5’ untranslated regions (UTR) of mRNAs, and regulation of RNA splicing (Figure 3(c)). Cell-based systems employ the use of a reporter gene, typically a fluorescent gene such as GFP or a luminescent gene such as firefly luciferase, either upstream, downstream, or interrupting a target RNA gene. This reporter gene acts as a read-out for disruption of RNA function. Reporter constructs are transfected into a given cell line, incubated with compounds of interest, and analyzed by plate reader or cytometry for alterations in fluorescence or luminescence.
Sex-biased transgenerational transmission of betaine-induced epigenetic modifications in glucocorticoid receptor gene and its down-stream BDNF/ERK pathway in rat hippocampus
Published in Nutritional Neuroscience, 2022
Yang Yang, Shu Yang, Yimin Jia, Chao Yin, Ruqian Zhao
Hippocampus is the key regulatory center for learning and memory consolidation, behavior and stress responses [1]. Glucocorticoid receptor (GR), a member of nuclear receptor subfamily 3, group C, is highly expressed in the hippocampus to mediate the central response to peripheral glucocorticoids under basal and stressful situations [2]. GR mRNA has different 5′-untranslated regions encoded by a series of alternative 1st exons. Nine and 10 GR exon 1 mRNA variants have been identified, respectively, in human [3,4] and in mice [5]. At least 11 GR exon 1 mRNA variants (exon 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11) have been found in rats [6]. The transcription of GR exon 1 mRNA variants is driven by their respective alternative promoters located upstream of each mRNA variant [7]. Although the alternatively spliced first exons are not translated, they play important roles in tissue-specificity of GR function. For instance, GR exon 1.7 variant is highly abundant in the hippocampus [6] and plays an important role in programming the stress responses [8]. GR and its mRNA variants in hippocampus are highly vulnerable to maternal and early-life factors, as maternal care increases hippocampal GR expression and decreases fear-related behavior in rat offspring [9]. Early-life social stresses induce GR exon 1.7 variant hypermethylation, which leads to downregulation of hippocampal GR expression and stress response dysregulation [10,11].
Current progress of miRNA-derivative nucleotide drugs: modifications, delivery systems, applications
Published in Expert Opinion on Drug Delivery, 2022
Charles Asakiya, Liye Zhu, Jieyu Yuhan, Longjiao Zhu, Kunlun Huang, Wentao Xu
The biogenesis of miRNAs begins with the post- or co-transcriptional processing of RNA polymerase/III transcripts[8]. In the canonical pathway, Drosha (a Class 2 ribonuclease III enzyme) and DiGeorge syndrome critical region 8 (DGCR8) enzymes break the primary miRNA (pri-miRNA) into the precursor miRNA (pre-miRNA) in the first step. The pre-miRNA is also cut by Dicer to make double-stranded RNAs, which are then linked to Argonaute (AGO) proteins to make the RNA-induced silencing complex (RISC). Exportin 5 then moves the pre-miRNA into the cytoplasm. There is evidence for miRNA-coding sequence and gene promoter interactions. The mechanism of miRNA’s attachment to the 5′ untranslated region (UTR) and coding areas to silence gene expression and the functional relevance of these interactions has also been reported. miRNAs can also be transported between cells to regulate translation and transcription. Recent research shows miRNA-mediated gene regulation is complex, and the disruption of miRNA activity is linked with disease onset and progression. The pool of possible targets is limited due to cell type-specific gene expression and compartmentalization.