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Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
While all three processes are tightly regulated, the rate-limiting step for translational control occurs at the initiation step. Translation initiation is a multi-step process regulated by eukaryotic initiation factors (eIFs) and culminates in formation of the 80S initiation complex. Prior to translation, the subunits of the ribosome are separate and the 40S subunit must be ‘primed’ by binding of a transfer RNA (tRNA). The tRNA contains the complementary sequence for the AUG start codon of mRNA and is also attached to the amino acid methionine. Proteins are synthesised beginning from the amine N-terminal and ending with a carboxyl C-terminal; therefore, all proteins begin with a methionine residue, although this is often removed after translation. The priming of the 40S ribosome is regulated in part by eIF3 and creates a 43S pre-initiation complex. Next eIF4 guides the 5’-end (named 5’-cap) of mRNA into the 43S complex and the ribosome proceeds along the mRNA until the start codon is found. Other eIFs then recruit the 60S subunit to create the 80S initiation complex, and synthesis of the polypeptide chain begins.
Cellular Responses to Adenovirus Entry
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Susanna Chiocca, Matthew Cotten
During lytic infection, adenovirus requires the infected cell to survive for only 24 to 48 hours, long enough to complete the synthesis of progeny virions, resulting in a 1000-fold amplification of the virus. Adenovirus has evolved strategies to alter the cellular antiviral responses within this time frame. For example, a translational inhibition due to activation of the interferon pathway occurs during adenovirus infection (55). This is thought to be due to activation of the interferon-inducible kinase p68 by double-stranded RNA molecules generated during the adenovirus life cycle. Kinase activity results in the inactivation of translation initiation factor eIF2α, and can potently downregulate translation. One adenovirus method of blocking this translational block involves the viral-encoded VA RNA molecule, which prevents double-stranded RNA activation of p68 (56-58; reviewed in 59). The adenovirus induction of interferon-responsive genes is also blocked at the transcriptional level by products of the E1A region (60-64). The E1A functions are not included in viral vectors. Furthermore, in the absence of E1A and viral DNA replication, full VA gene expression is not achieved.
Translation
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
The MS2 RNA was used as a standard model for the in vitro translation by a systematic study on the selection of the mRNA translation initiation region by E. coli ribosomes, when genes specifying model mRNAs of minimal size and coding capacity, with or without the SD sequence, were assembled, cloned, and transcribed in high yields (Calogero et al. 1988). This study led to the logical suggestion that the function of the SD interaction was to ensure a high concentration of the initiation triplet near the ribosomal peptidyl-tRNA binding site, whereas the selection of the translational start was achieved kinetically, under the influence of the initiation factors, during decoding of the initiator tRNA.
TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2022
Yara Al Ojaimi, Audrey Dangoumau, Hugo Alarcan, Rudolf Hergesheimer, Patrick Vourc’h, Philippe Corcia, Débora Lanznaster, Hélène Blasco
Under normal physiological conditions, TDP-43 mainly resides in the nucleus with a small fraction constantly shuttling between the nucleus and the cytoplasm. In the nucleus, TDP-43 regulates gene transcription through its association with sites of transcription and its interaction with transcription regulators [15]. TDP-43 also participates in the repair of double-stranded DNA breaks [16]. In addition, it is important for pre-mRNA splicing through the regulation of exon skipping and inclusion, the repression of cryptic exons, and the regulation of its own mRNA [3]. The autoregulation of TDP-43 occurs via the nuclear fraction of the protein which normally promotes the splicing of cryptic introns in the TDP-43 pre-mRNA and subsequent nonsense-mediated mRNA decay (NMD) [7]. TDP-43 was also shown to be involved in the processing of non-coding RNA such as the biogenesis of micro-RNA (miRNA) and the association with long non-coding RNA (lncRNA) [17,18]. In the cytoplasm, TDP-43 controls the stability of the mRNA through its binding to 3’ untranslated regions. It is also essential for the regulation of mRNA translation by associating with translation initiation and elongation factors or recruiting translational inhibiting complexes [19]. Moreover, in neurons TDP-43 is involved in mRNA trafficking, particularly in dendrites and axons [20].
Adeno-associated virus (AAV) capsid engineering in liver-directed gene therapy
Published in Expert Opinion on Biological Therapy, 2021
Esther Rodríguez-Márquez, Nadja Meumann, Hildegard Büning
The AAV capsid is an icosahedron of approximately 25 nm in diameter [22,23]. The three VPs are encoded in a single gene, cap, and share most of their amino acid sequence (‘VP3 common region’). Specifically, VP1 and VP2 are the N’-terminal extensions of VP3. They are produced from a common mRNA via alternative splicing and distinct translation initiation codons. The actual capsid is formed by the common VP3 region present in all the VPs, while the N’-termini of VP1 and VP2 contain functional domains such as a phospholipase A2 (PLA2) homology region in the VP1 unique part or basic regions (BRs) in VP1 and VP2 that serve as nuclear localization sequences. Following virus or vector particle assembly, these N’-termini are directed toward the capsid interior [23], but become exposed during cell infection.
Proteogenomic interrogation of cancer cell lines: an overview of the field
Published in Expert Review of Proteomics, 2021
The discovery of alternative ORFs often starts with ribosome profiling (RP) or RIBO-seq, which probes the interaction between a ribosome and an mRNA in translation [72,73]. As RP can show exact ribosomal location, especially at translation initiation sites, protein sequences from alternative ORFs can be obtained after three-frame translation from the novel start codons. Detecting protein products from alternative ORFs requires searching mass spectra against a custom database containing RP–predicted protein sequences [74]. RP itself has been utilized to uncover alternative ORFs in CCLs, which indicate aberrant protein expression [75], and the detection of their protein products corroborates the identity of these alternative ORFs [74,76–78]. In fact, CCLs are one of the few cancer models on which RP can be carried out as the samples must be treated with ribosome inhibitor during culturing prior to analysis, which is not feasible on tissue samples.