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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
The primary transcript produced by RNA polymerase II undergoes post-transcriptional processing to become mRNA that can be translated into protein. Most human genes consist of multiple exons, which is the part of the gene that encodes the protein interspersed by introns or intervening sequences. Introns are removed by spliceosomes and, depending on which exons are retained, different splice variants of the gene can be created. A well-known example relevant to exercise physiology is the alternative splicing of the IGF-I gene to create mechano-growth factor (MGF, also referred to as IGF-IEc in humans or IGF-IEb in rodents), which was discovered by Geoffrey Goldspink’s group in the late 1990s (62). The activity of spliceosomes is in part regulated by proteins that recognise and mark different splice sites, but as yet it is unclear as to how exercise regulates alternative splicing.
Disease Prediction and Drug Development
Published in Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam, Introduction to Computational Health Informatics, 2019
Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam
During the transcription process, a transcriptase binds to the promoter-region, strips the hydrogen bonds between the A≡T and G≡C pairs and separates the strand. In the next phase, a thymine molecule (“T”) is substituted by an uracil (“U”) molecule. The transcription of a bacterial gene is straightforward due to the absence of introns. However, in eukaryotes, the primary transcript after the transcription process also includes the corresponding intron version. The primary transcript goes through an additional process of splicing that removes the intron-part from the primary transcript and joins the exons to create the corresponding mRNA. The process of transcription of DNA to mRNA for eukaryotic gene is illustrated in Figure 10.5.
Analysis of Small RNA Species: Phylogenetic Trends
Published in S. K. Dutta, DNA Systematics, 2019
Mirko Beljanski, Liliane Le Goff
Small RNAs have also been found in Ehrlich ascites tumor cells. Electrophoresis on polyacrylamide gel has shown that five of them migrate more slowly than 5S rRNA and three components migrate between 5S and 4S RNA. All these RNAs are localized in the nucleus and account for 0.7 to 2.9% of total nuclear RNAs.135 These small RNAs have a stability comparable to rRNAs. Their synthesis is more or less efficiently inhibited with the actinomycin D that inhibits the transcription of rRNAs and 5S rRNA from DNA. It remains to be seen whether RNAs are generally the primary transcript and what their biological significance may be.
The MALAT1-breast cancer interplay: insights and implications
Published in Expert Review of Molecular Diagnostics, 2023
MALAT1 is a lncRNA that is expressed at high levels in the genome, with a length of about 8,000 nucleotides. It is the first lncRNA identified to be linked with metastasis and survival in NSCLC. Despite its large size, MALAT1 lacks an open reading frame and is thus not translated into a protein in vitro. Rather, it affects how genes are expressed and changes primary transcripts in a similar manner across mammals [13]. Several types of cancer in humans have been linked to mutations in MALAT1, including lung [14,15], breast [16,17], bladder, osteosarcoma [18,19], colorectal [20,21], and liver cancer [22,23]. MALAT1 has been shown to localize to nuclear speckles through in vitro studies [24]. Additionally, knockdown experiments have revealed that it modulates alternative pre-messenger RNA splicing [25]. Further tests indicated no significant differences between Malat1 knockout mice and wild-type mice in terms of phenotypic changes. The deletion of Malat1 did not affect the expression of genes, nuclear speckles, splicing factors, or alternative pre-mRNA splicing in mouse tissues [26,27].
Role of computational and structural biology in the development of small-molecule modulators of the spliceosome
Published in Expert Opinion on Drug Discovery, 2022
Riccardo Rozza, Pavel Janoš, Angelo Spinello, Alessandra Magistrato
While consensus splicing (the process of retaining each and only the exonic sequences in the pre-mRNA transcript) was long believed to be the only splicing mechanism, it is now well known that 94% of human genes are alternatively spliced through exon inclusion or skipping, the differential use of alternative 5’SS and 3’SS, and intron retention (Figure 1(c)). These variations, referred to as alternative splicing (AS), lead to different protein-coding mRNAs thus resulting in functionally distinct proteins synthesized from a single gene. This enormously expands the coding potential of the primary transcripts, and greatly enhances proteome diversity. Nevertheless, AS is more susceptible to splicing deregulation since it relies on recognizing weakly-binding pre-mRNA sequences (sequences with reduced base pair complementarity to the snRNAs as compared to consensus ones). As a result, abnormal changes in AS (i.e. aberrant splicing) are frequently observed in human diseases such as different types of cancers, neurological diseases, spinal muscular atrophy, immunological and celiac disease, psoriasis, asthma, inflammatory response, viral infections, cardiovascular disease, and diabetes mellitus [12].
Antisense Oligonucleotide Therapy for Ophthalmic Conditions
Published in Seminars in Ophthalmology, 2021
Kevin Ferenchak, Iris Deitch, Rachel Huckfeldt
A review of the pathway from gene to protein is helpful in understanding the mechanism of AON. Genes are composed of introns and exons, and exons are the sequences of base pairs that are expressed. DNA is transcribed in the nucleus to a complementary strand of pre-mRNA. Before leaving the nucleus, non-coding intronic regions are excised from this primary transcript and exons are spliced together at a spliceosome. The mRNA is then transported to the cytoplasm where it is translated on ribosomes in sets of three bases into amino acids, which aggregate to form proteins that are critical for the health and function of a cell. Misspellings of even a single base pair can cause a pathogenic shift in the sequence of amino acids, leading to aberrant splicing and a malfunctioning protein. Studies have estimated that more than 10% of genetic disorders are caused by single base pair mutations at exon-intron junctions that alter splicing.14,15 Alterations in both exons and introns can be associated with pathogenic changes in the genetic sequence such as nonsense mutation causing a premature termination, missense mutations changing an amino acid, and frameshift mutations caused by insertion or deletion of a set of base pairs not divisible by three, thus altering every amino acid downstream.