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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.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In eukaryotic organisms, pre-mRNA is transcribed in the nucleus. Introns are then spliced out, and the mature mRNA exported from the nucleus to the cytoplasm. The small subunit of the ribosome usually starts by binding to one end of the mRNA and is joined there by various other eukaryotic initiation factors, thus forming the initiation complex. The initiation complex scans along the mRNA strand until it reaches a start codon, and then the large subunit of the ribosome attaches to the small subunit and translation of a protein begins. Backbone-modified oligomers (Figure 5.95) can bind to the RNA and block this process. Structures of peptide nucleic acids (PNAs), Morpholino Oligonucleotides and the ribose sugar modifications of locked nucleic acids (LNAs) in comparison to DNA.
Severe Congenital Neutropenia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Specifically, through interaction with elongation factor-like GTPase 1, SBDS triggers release of eukaryotic initiation factor 6 (EIF6) from 60S pre-ribosomes in the cytoplasm and facilitates 80S ribosome assembly and EIF6 recycling to the nucleus for 60S rRNA processing and nuclear export. Homozygous mutations within SBDS cause Shwachman−Bodian−Diamond syndrome, which manifests as thrombocytopenia, anemia, and aplastic anemia (14% of SCN cases).
Toxicity of the herbicides used on herbicide-tolerant crops, and societal consequences of their use in France
Published in Drug and Chemical Toxicology, 2022
In Arabidopsis thaliana, up-regulated genes are those encoding enzymes involved in the metabolization of herbicides such as cytochrome P450 (CYP), GST and UDP glycosyl transferases (UGT), and allowing detoxification such as ATP-binding cassette (ABC) transporters and multidrug resistance (MRP) and toxin extrusion (MATE) protein families, and the iron superoxide dismutase Fe-SOD genes (FSD). Also up-regulated genes comprise those encoding ribosome associated proteins or protein synthesis initiation factors (eIF4A, eIF4E and eIF5), and some involved in amino acid synthesis. The mitochondrial function is also impacted since the genes encoding mitochondrial genes alternative oxidases ATAOX1a and ATAOX1b, along with two mitochondrial NADH dehydrogenases, NDB2 and NDB4 are up-regulated. Down-regulated genes are those involved in cell wall biosynthesis, along with genes involved in the neutralization of the oxidative stress such as those encoding copper-zinc superoxide dismutases Cu/ZnSOD (CSD), ascorbate peroxidases (APX), and glutathione peroxidases (GPX).
Research Progress of circRNAs in Inflammatory Mechanisms of Diabetic Retinopathy: An Emerging Star with Potential Therapeutic Targets
Published in Current Eye Research, 2022
Shuai He, Chufeng Gu, Tong Su, Qinghua Qiu
Because of the special structure of circRNAs without a 5ʹ cap or a 3ʹ poly A tail, which is indispensable for classical cap-dependent translation, circRNAs have been suggested to be able to be translated in cap-independent manners.46 On the one hand, there are available sequences serving as internal ribosome entry sites (IRESs) of circRNAs to facilitate direct combination with the ribosome or the initiation factors in the course of translation.47–49 To date, only a small number of circRNAs such as circ-FBXW7, circPINTexon2 and circ-SHPRH have been reported to bind with ribosomes for translation.50,51 Specifically, Yang, Y. et al. proved that the peptides FBXW-185aa, PINT87aa and SHPRH-146aa originated from circ-FBXW7, circPINTexon2 and circ-SHPRH, respectively and were considered to inhibit tumor biogenesis in human glioblastoma.52,53 This translation mechanism of circRNAs shares the same initiation codons with the hosting mRNAs, which enables these polypeptides to be derived from circRNAs to compete with mRNA-encoded proteins and affect biological function.51 On the other hand, circRNA translation can also be induced by m6A modification in the 5′ untranslated region (UTR),54,55 proved by the fact that m6A demethylase fat mass hindered the process of translation and decreased the efficiency.56
Genetic diseases mimicking multiple sclerosis
Published in Postgraduate Medicine, 2021
Chueh Lin Hsu, Piotr Iwanowski, Chueh Hsuan Hsu, Wojciech Kozubski
Vanishing white disease (VWD), as suggested by its name, is a disease that involves white matter in the central nervous system, where the nerves fibers are located. Any mutations in one of the five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5) coding translation initiation factor eIF2B have been identified as the etiology of the disease. Astrocytes play an important role in white matter functioning, but fail to fully mature and express immature markers nestin and CD44 on their progenitor cells in VWD. The resulting effect is the lack of support for oligodendrocytes in transforming into myelin-producing cells in CNS [126,127]. The other proposed patho-mechanism of VMD is that the incompetent eIF2B fails to meet up the body’s needs under physiologic stress, which results in the consequent failure to restore microglia-astrocyte impairments [128]. The diagnosis can be made among patients with typical clinical features and MRI findings of VWD. Genetic testing is recommended but not necessary as 90% of diagnosed VWD patients show mutations in one of the five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) [126–128].