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Platelet-Derived Growth Factor
Published in Jason Kelley, Cytokines of the Lung, 2022
James P. Fabisiak, Jason Kelley
Nucleotide sequencing of the lengthy 5′ flanking region of the c-sis gene revealed a traditional TATAAA promoter element 24-base pairs (bp) upstream from the mRNA start site, a putative Sp1 binding site, but no CAAT box (van den Ouweland et al., 1987; Rao et al., 1988). It does encode sequences that act as translational inhibitors (Rao et al., 1988). A single atypical polyadenylation site within the 3′ UTR is in concordance with the presence of a single species of mRNA transcript of 3.8–4.0 kilobases (kb) seen in positive cells. The 3′ UTR contains (A + U)-rich consensus sequences similar to those described by Shaw and Kamen (1986), which appear to function in determining the stability of several rapidly degraded cytokine transcripts, through the action of a specific exonuclease. More recently, the recognition of other positive and negative regulatory elements within the 5′ UTR have suggested additional mechanisms for regulation of PDGF-B gene expression (Rao et al., 1986; Pech et al., 1989; Franklin et al., 1991).
Cellular and Immunobiology
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Masood Moghul, Sarah McClelland, Prabhakar Rajan
Pre-mRNA is matured to form mRNA.5' capping protects degradation by RNase by adding a methylated guanine cap.Polyadenylation stabilises RNA by adding a poly(A) tail to the 3' end.Splicing is where non-coding introns are removed by spliceosome excision. Coding exons are joined together by ligation.
Hemoglobinopathies
Published in Victor A. Bernstam, Pocket Guide to GENE LEVEL DIAGNOSTICS in Clinical Practice, 2019
Variations in the clinical phenotype of β-thalassemia have been traced to mutations in the regulatory sequences outside the b-globin gene, which control the transcriptional efficiency of the b-globin genemutations affecting RNA processing: RNA modification at the cap (7-methylguanosine) siteRNA cleavagepolyadenylationsplicingmutations affecting translation of the mRNA into globin
The discovery and development of RNA-based therapies for treatment of HIV-1 infection
Published in Expert Opinion on Drug Discovery, 2023
Michelle J Chen, Anne Gatignol, Robert J. Scarborough
U1 small nuclear RNA (U1 snRNA) interference (U1i) is a distinct gene silencing mechanism inspired by the naturally occurring eukaryotic U1 ribonucleoprotein complex that plays a role in precursor mRNA splicing [32,168]. The U1 small nuclear ribonucleoprotein (snRNP) complex consists of seven spliceosomal Smith (Sm) proteins, three U1-specific proteins, and the 164 nt U1 snRNA folded into a four stem-loop structure. This complex is important for defining the 5’ splice sites and regulating 3’-end processing on pre-mRNAs. By binding to cis-elements up- or down-stream of the polyadenylation site, U1 snRNPs can inhibit polyadenylation. Transcripts lacking the polyA tail are unstable and degraded by host cell machinery, thus preventing the maturation of pre-mRNAs. Molecular engineering of the U1 snRNA exploits this natural repression function to silence gene expression. The U1 snRNA is modified at its 5’ end to code for a ~10 nt sequence complementary to the target RNA [169]. The resulting synthetic U1i RNA is then cloned under the U1 promoter and expressed in the cell where it transits to the nucleus to recruit U1 snRNPs to the target RNA, resulting in sequence-specific post-transcriptional gene silencing (Figure 4A).
An overview of rational design of mRNA-based therapeutics and vaccines
Published in Expert Opinion on Drug Discovery, 2021
Kenneth K.W. To, William C.S. Cho
In eukaryotic cells, the mRNA poly(A) tail recruits the poly(A)-binding protein and subsequently the eIF4G translation initiation complex to mediate translation [78]. For IVT mRNA used for mRNA therapeutics, the poly(A) tail is either encoded in the DNA template or added enzymatically to the mRNA after the in vitro transcription procedure as a separate step. DNA template-encoded poly(A) has the advantage of producing defined and reproducible poly(A) length [79]. In contrast, enzymatic post-transcriptional polyadenylation of mRNA could produce transcripts with different poly(A) lengths and therefore may not meet regulatory requirements [80]. Enzymatic polyadenylation of mRNA has to be performed under alkaline conditions. Since mRNA is susceptible to alkaline hydrolysis, the enzymatic polyadenylation method is known to produce mRNA of inferior quality, especially with longer transcripts (>3 kb) [81].
First Report of the 3'-Untranslated Region +1506 (A>C) [NM_000518.5: c.*32A>C] mutation on the β-Globin Gene in the Indian Population
Published in Hemoglobin, 2021
Aditi Sen, Venu Seenappa, Prantar Chakrabarti, Tuphan Kanti Dolai
The adenylate uridylate (AU-rich) elements (AREs) are the most common regulatory elements in the 3′-UTR responsible for mRNA (de)stabilization and alternative pre-mRNA processing. A basic motif in AREs is represented by the pentamer ‘AUUUA’ that occurs in variable-length repetitions in the regions rich for uracil and interspersed with adenine. Usually, they encompass the facilitation of the deadenylation process resulting in the accelerated shortening of polyadenylation (polyA) tail, which is crucial for mRNA stability [5]. Therefore, a mutation in this region might be involved in the reduction of β-globin chain production. Here, we report a very rare mutation located in the first AU motif of 3′-UTR of the β-globin gene for the first time in India during mutation screening for prenatal diagnosis (PND) of an at-risk couple, and attempt to elucidate the resulting phenotype.