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Non-VLPs
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
It is notable in this context that the MS2-based tethering approach was used for the identification of the splicing repressor domain in polypyrimidine tract-binding protein, a splicing regulator, and for the further elucidation of its role in the splicing process (Wagner and Garcia-Blanco 2002; Gromak et al. 2003; Robinson and Smith 2006; Spellman and Smith 2006; Sharma et al. 2008; Kafasla et al. 2012; Martin et al. 2013).
Introduction to Molecular Biology
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
An intron in the pre-mRNA molecule often begins with nucleotides GU and finishes with AG, which is preceded by a pyrimidine-rich sequence called polypyrimidine tract. The splicing reaction occurs in two steps, (Fig. 11) in a region called branchpoint sequence, which is situated 10 to 40 nucleotides upstream of the polypyrimidine tract. The first step is the attack of the G residue in the 5′ splicing site by the 2′-hydroxyl of the A residue in branchpoint. It results in the formation of a lariat and a free exon. In the second step, the 3′ end G residue of the intron is cleaved, which brings the two exons together and release the intron in a lariat form. This process generates a mature mRNA molecule that can further be exported into the cytosol for the translation process.
RNA-based drug discovery for spinal muscular atrophy: a story of small molecules and antisense oligonucleotides
Published in Expert Opinion on Drug Discovery, 2023
Blanca Torroba, Natsuko Macabuag, Elisabeth M. Haisma, Amy O’Neill, Maria E. Herva, Roxana S. Redis, Michael V. Templin, Lauren E. Black, David F. Fischer
The molecular mechanism for SMN1 and SMN2 exon 7 splicing was characterized by several groups in the late 1990s and early 2000s [22–25]. Regulation of exon 7 splicing for SMN1 and SMN2 comprises splicing signals at or near the exon-intron junctions of the pre-mRNA, including the 5’ and 3’ splice site, polypyrimidine tract, and branch point sequence in intron 6, recognized by the spliceosome [24] (Figure 2(a)). Further characterization unveiled that exon 7 in both SMN1 and SMN2 has a weak 5’ splice site and, therefore, additional signals are required for an efficient exon recognition [8]. Those additional regulatory players involve positive cis-elements, such as exonic and intronic splicing enhancers (ESEs and ISEs), as well as negative cis-elements such as exonic and intronic splicing silencers (ESSs and ISSs). The positive cis-elements are binding sites for splicing activator proteins, such as the serine-arginine-rich (SR) protein, SRSF1, and the SR-like protein, Tra2-β1 [22,25]. The negative cis-elements are the binding sites for splicing repressors, such as heterogeneous nuclear ribonucleoproteins (hnRNP) A1 and A2 proteins [24].
The MAP kinase-interacting kinases (MNKs) as targets in oncology
Published in Expert Opinion on Therapeutic Targets, 2019
Jianling Xie, James E. Merrett, Kirk B. Jensen, Christopher G. Proud
Several studies have reported additional MNK substrates, although in vivo data are still lacking (Figure 3). Buxade et al. [41] showed that MNKs phosphorylate HnRNP A1, a protein which plays roles in splicing and other aspects of RNA metabolism. MNKs were found to phosphorylate HnRNP A1 at two sites in vitro and in Jurkat T-cells. MNK-mediated phosphorylation of HnRNP A1 decreases its affinity for the mRNA for tumour necrosis factor-α (TNFα), potentially contributing to the ability of MNKs to enhance TNFα production by these cells [41]. The same group also showed that MNKs can phosphorylate the polypyrimidine tract-binding protein-associated splicing factor (PSF) [42]. The physiological significance of the MNK-mediated phosphorylation of PSF remains to be established.
Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?
Published in Expert Opinion on Orphan Drugs, 2021
Ruofan Connie Han, Lewis E. Fry, Ariel Kantor, Michelle E. McClements, Kanmin Xue, Robert E. MacLaren
In eukaryotic mRNA processing, splicing of pre-mRNA is directed by interactions between the spliceosome (a complex of proteins and small nuclear RNAs which facilitates intronic excision) and the 5ʹ donor, branch, and 3ʹ acceptor sites within each intron. Typically, the splice donor site (5ʹ end of the intron) includes a GU sequence, followed by a relatively unconserved section which is followed by the branchpoint and a polypyrimidine tract, a sequence rich in pyrimidines, and terminating in the acceptor site at the 3ʹ-end, usually an AG sequence. Mutations within these key areas of the intron can lead to the formation of a cryptic splice site, able to redirect the pre-mRNA’s interactions with the spliceosome and resulting in the insertion of an aberrant exon.