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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Several studies have demonstrated that protein–protein interactions control the expression of HDACs through: (a) alternative RNA splicing; (b) the modulation of the availability of cofactors; (c) varied subcellular localization; and (d) different degrees of proteolytic processing (Gallinari et al., 2007; Seto and Yoshida, 2014). Individual HDAC proteins, especially HDAC1 and HDAC2, are generally low in enzyme activity; however, when associated with protein complexes such as Sin3, nucleosome remodeling and deacetylase (NuRD), and co-repressor for element-1-silencing transcription factor (CoREST), they exhibit enhanced function, indicating the importance of protein–protein interactions in controlling their biological activity (Banks et al., 2018).
The Inducible Defense System: Antibody Molecules and Antigen-Antibody Reactions
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Within the same B cell, DNA recombination of the H chain V region loci also takes place. The H chain variable region is coded for by three different DNA segments, namely the Variable (V) which codes for amino acids 1 to 95, the Diversity (D) segments which code for one to fourteen different amino acids, and the Joining (J) segment which codes for the remainder of the H chain V region. In humans, there are an estimated fifty-one functional heavy chain V segments, twenty-seven D segments, and six J segments. Thus, by the random assortment of these segments, 8,262 different heavy chain VDJ combinations can be made. An especially high amount of diversity is found in the third CDR region of the H chain as both the D and J segments aid in coding for this area. Downstream from the V coding region are located DNA sequences which code for each of the H chain constant region isotypes (e.g., μ, δ, γ, α, and ε). Following recombination, a primary RNA transcript is made which contains information for the V region, the μ constant region and the δ constant region. The RNA transcript is produced, introns are excised, and RNA splicing takes place resulting in two mRNA transcripts. One codes for an IgM and one for an IgD molecule. This process explains how the same variable region can become associated with two different constant regions. Once the recombination process is complete, the B cell has committed itself to the production of a unique L and a unique H chain that pair to form an antibody molecule capable of interacting with a single epitope.
Regulation of the RAT Thiostatin Gene
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Timothy J. Cole, Gerhard Schreiber
The mode of mRNA splicing for the thiostatin and kininogen genes is depicted in Figure 4. The kininogen gene is transcribed into both HMW and LMW kininogen mRNA, while the thiostatin genes only give rise to a LMW thiostatin mRNA. Kakizuka et al.29,30 have suggested an RNA splicing model which proposes that stretches of repeated sequences exist in exon 10 of the kininogen gene that are complementary to the U1 snRNA of the spliceosome. This would allow formation of a stable, nonfunctional spliceosome and allow time for the pre-mRNA to undergo polyadenylation at the end of the HMW-encoding exon sequence and form a HMW-kininogen mRNA. The HMW-specific sequences of exon 10 are therefore not always spliced out. In the case of the thiostatin genes, mutations (described above) could disrupt this proposed interaction with the U1 snRNA and thereby prevent formation of a stable spliceosome. Therefore, a functional processive spliceosome arises and efficiently splices the pre-mRNA into LMW-thiostatin mRNA.
Emerging medicines to improve the basic defect in cystic fibrosis
Published in Expert Opinion on Emerging Drugs, 2022
Isabelle Fajac, Isabelle Sermet-Gaudelus
Another therapeutic use of ASOs in CF could be for mutations involving aberrant exon splicing. RNA splicing is the process by which introns are removed from precursor mRNA. Splicing mutations disrupt intronic or exonic splicing motives. They lead to skipping over the exon and very commonly generate PTC because of reading frame disruption. They result in aberrant mRNA and non-functional protein [58]. Some other mutations alter regulatory splicing motives throughout the gene and lead to variable levels of both aberrantly and correctly spliced transcripts from these mutated alleles. This group includes the splicing mutations 3849 + 10Kb C > T. This mutation is associated with reduced amount of normal CFTR, and a correlation was found between the amount of correctly spliced CFTR transcripts and lung function. This finding highlights the potential of splicing modulation as a therapeutic approach [59]. ASOs act by inhibiting or activating specific splicing events by a steric blockade of the recognition of specific splicing elements. They were shown to modulate splicing in cells with various CFTR splicing mutations and improve CFTR activity in bronchial epithelial cells [60,61]. No evaluation in a clinical trial of ASOs for CFTR splicing mutations has been undertaken so far. But importantly, ASO-based drugs modulating splicing are already approved for spinal muscular atrophy and Duchenne muscular dystrophy. This highlights the potential of such therapies for CF (Table 1).
Ribosomopathies and cancer: pharmacological implications
Published in Expert Review of Clinical Pharmacology, 2022
Gazmend Temaj, Sarmistha Saha, Shpend Dragusha, Valon Ejupi, Brigitta Buttari, Elisabetta Profumo, Lule Beqa, Luciano Saso
Ribosome biogenesis begins with rRNA synthesis in the nucleolus, and the first step involves the formation of a preinitiation complex (PIC) around the rDNA promoter region. During ribosome biogenesis, RNA polymerase I (Pol I) is shown to transcribe rRNA genes into a single polycistronic transcript that is cleaved into 18S, 5.8S, and 28S rRNAs. During processing, many small nucleolar ribonucleoparticles (snoRNP) facilitate the modification of numerous rRNA residues [29,30], such as pseudouridylation and methylation (M), which plays pivotal roles in ribosomal maturation. These RNA transcripts in 5’ site form the 90S ‘processome’ complex. This complex 90S was cleaved to form pre-40S and 60S particles. In the nucleoplasm, RNA polymerase II (Pol II) and RNA polymerase III (Pol III) are involved in the transcription of the ribosomal protein (RPs) and 5S rRNA genes [31]. (Figure 1). Ribosomal proteins (RPs) after that are shown to stabilize small and large subunits, rRNA processing, pre-ribosome transport, RNA folding, and interaction of other factors that are required for ribosome synthesis or translation [32]. The RNA splicing process is very complex and has been described by many authors (see reviews by Watkins and Bohnsack [33], Lafontaine [290], and Rahhal and Seto [291].
Splicing deregulation, microRNA and notch aberrations: fighting the three-headed dog to overcome drug resistance in malignant mesothelioma
Published in Expert Review of Clinical Pharmacology, 2022
Dario P. Anobile, Giulia Montenovo, Camilla Pecoraro, Marika Franczak, Widad Ait Iddouch, Godefridus J Peters, Chiara Riganti, Elisa Giovannetti
Pre-mRNA is only functional for protein synthesis after the removal of introns and when the exons are spliced together. The spliceosome is responsible for splicing out introns from pre-transcribed mRNA (Figure 4). The splicing process is essential for the regulation of gene expression in eukaryotes. Mutations or differentially expressed splicing factors (SF) that form the spliceosome are common in cancer and lead to splicing deregulation such as exon skipping, intron retention and alternative splicing sites. This results in the production of aberrant mRNA splicing patterns. which affect biological processes related to chemoresistance, including decreased transport of the anticancer drugs into the intracellular space, impaired conversion to an active metabolite, altered regulation of target gene transcription and apoptosis [118]. Moreover, alternative splicing leads the formation of cancer-specific splicing isoforms, which produce transcriptome changes relevant for many processes underlying tumor biology [119]. For instance, an incorrect splicing of BAP1 mRNA can impair correct protein formation, as described by Morrison and colleagues, who identified a novel homozygous substitution mutation, BAP1 c.2054 A&T (p.Glu685Val). This causes aberrant splicing and premature truncation of the BAP1 protein, resulting in genomic instability [18].