Post-transcriptional regulation
Post-transcriptional regulation is the control of
Mechanism
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After being produced, the stability and distribution of the different transcripts is regulated (post-transcriptional regulation) by means of
of the transcript. In short, the dsRNA sequences, which will be broken down into siRNA inside of the organism, will match up with the RNA to inhibit the gene expression in the cell.Modulating the capping, splicing, addition of a
- mRNA to a three prime end by 5'-5' linkage, which protects the mRNA from 5' exonuclease, which degrades foreign RNA. The cap also helps in ribosomal binding. In addition, it represents a unique mark for a correct gene. Therefore, it helps to select the mRNA that is going to be translated.
- RNA splicing removes the introns, noncoding regions that are transcribed into RNA, in order to make the mRNA able to create proteins. Cells do this by spliceosomes binding on either side of an intron, looping the intron into a circle and then cleaving it off. The two ends of the exons are then joined.
- Addition of poly(A) tail otherwise known as polyadenylation. That is, a stretch of RNA that is made solely of adenine bases is added to the 3' end, and acts as a buffer to the 3' exonuclease in order to increase the half-life of mRNA. In addition, a long poly(A) tail can increase translation. Poly(A)-binding protein (PABP) binds to a long poly(A) tail and mediates the interaction between EIF4E and EIF4G which encourages the initiation of translation.
- RNA editing is a process which results in sequence variation in the RNA molecule, and is catalyzed by enzymes. These enzymes include the adenosine deaminase acting on RNA (ADAR) enzymes, which convert specific adenosine residues to inosine in an mRNA molecule by hydrolytic deamination. Three ADAR enzymes have been cloned, ADAR1, ADAR2 and ADAR3, although only the first two subtypes have been shown to have RNA editing activity. Many mRNAs are vulnerable to the effects of RNA editing, including the glutamate receptor subunits GluR2, GluR3, GluR4, GluR5 and GluR6 (which are components of the AMPA and kainate receptors), the serotonin2C receptor, the GABA-alpha3 receptor subunit, the tryptophan hydroxylase enzyme TPH2, the hepatitis delta virus and more than 16% of microRNAs. In addition to ADAR enzymes, CDAR enzymes exist and these convert cytosines in specific RNA molecules, to uracil. These enzymes are termed 'APOBEC' and have genetic loci at 22q13, a region close to the chromosomal deletion which occurs in velocardiofacial syndrome (22q11) and which is linked to psychosis. RNA editing is extensively studied in relation to infectious diseases, because the editing process alters viral function.
- mRNA Stability can be manipulated in order to control its half-life, and the poly(A) tail has some effect on this stability, as previously stated. Stable mRNA can have a half-life of up to a day or more which allows for the production of more protein product; unstable mRNA is used in regulation that must occur quickly. mRNA stability is an important factor that is based on mRNA degradation rates.[4]
- Nuclear export. Only one-twentieth of the total amount of RNA leaves the nucleus to proceed with translation. The rest of the RNA molecules, usually excised introns and damaged RNAs, are kept in the nucleus where they are eventually degraded. mRNA only leaves the nucleus when it is ready to keep going, which means that nuclear export is delayed until the processing is complete. As an interesting fact, there are some mechanisms that attack this nuclear export process to regulate gene expression. An example of regulated nuclear transport of mRNA can be observed in HIV.[1]
Transcription attenuation
Transcription attenuation is a type of prokaryotic regulation that happens only under certain conditions. This process occurs at the beginning of RNA transcription and causes the RNA chain to terminate before gene expression.[5] Transcription attenuation is caused by the incorrect formation of a nascent RNA chain. This nascent RNA chain adopts an alternative secondary structure that does not interact appropriately with the RNA polymerase.[1] In order for gene expression to proceed, regulatory proteins must bind to the RNA chain and remove the attenuation, which is costly for the cell.[1][6]
In prokaryotes there are two mechanisms of transcription attenuation. These two mechanisms are intrinsic termination and factor-dependent termination.
- In the intrinsic termination mechanism, also known as
- In factor-dependent termination, which is a protein factor complex containing Rho factor, is bound to a segment from the RNA chain transcript. The Rho complex then starts looking in the 3' direction for a paused RNA polymerase. If the polymerase is found, the process immediately stops, which results in the abortion of RNA transcription.[5][6] Even though this system is not as common as the one described above, there are some bacteria that uses this type of termination, such as the tna operon in E.coli.[7]
This type of regulation is not efficient in eukaryotes because transcription occurs in the nucleus while translation occurs in the cytoplasm. Therefore, the mechanism is not continued and it cannot execute appropriately as it would if both processes happen on the cytoplasm.[8]
MicroRNA mediated regulation
MicroRNAs (miRNAs) appear to regulate the expression of more than 60% of protein coding genes of the human genome.[9] If an miRNA is abundant it can behave as a "switch", turning some genes on or off.[10] However, altered expression of many miRNAs only leads to a modest 1.5- to 4-fold change in protein expression of their target genes.[10] Individual miRNAs often repress several hundred target genes.[9][11] Repression usually occurs either through translational silencing of the mRNA or through degradation of the mRNA, via complementary binding, mostly to specific sequences in the 3' untranslated region of the target gene's mRNA.[12] The mechanism of translational silencing or degradation of mRNA is implemented through the RNA-induced silencing complex (RISC).
Feedback in the regulation of RNA binding proteins
In metazoans and bacteria, many genes involved in post-post transcriptional regulation are regulated post transcriptionally.[15][16][17] For Drosophila RBPs associated with splicing or nonsense mediated decay, analyses of protein-protein and protein-RNA interaction profiles have revealed ubiquitous interactions with RNA and protein products of the same gene.[17] It remains unclear whether these observations are driven by ribosome proximal or ribosome mediated contacts, or if some protein complexes, particularly RNPs, undergo co-translational assembly.
Significance
This area of study has recently gained more importance due to the increasing evidence that post-transcriptional regulation plays a larger role than previously expected. Even though protein with
Furthermore, RNA found in the nucleus is more complex than that found in the cytoplasm: more than 95% (bases) of the RNA synthesized by RNA polymerase II never reaches the cytoplasm. The main reason for this is due to the removal of introns which account for 80% of the total bases.[20] Some studies have shown that even after processing the levels of mRNA between the cytoplasm and the nucleus differ greatly.[21]
Developmental biology is a good source of models of regulation, but due to the technical difficulties it was easier to determine the transcription factor cascades than regulation at the RNA level. In fact several key genes such as nanos are known to bind RNA but often their targets are unknown.
microRNA role in cancer
Deficiency of expression of a DNA repair gene occurs in many cancers (see DNA repair defect and cancer risk and microRNA and DNA repair). Altered microRNA (miRNA) expression that either decreases accurate DNA repair or increases inaccurate microhomology-mediated end joining (MMEJ) DNA repair is often observed in cancers. Deficiency of accurate DNA repair may be a major source of the high frequency of mutations in cancer (see mutation frequencies in cancers). Repression of DNA repair genes in cancers by changes in the levels of microRNAs may be a more frequent cause of repression than mutation or epigenetic methylation of DNA repair genes.
For instance, BRCA1 is employed in the accurate homologous recombinational repair (HR) pathway. Deficiency of BRCA1 can cause breast cancer.[24] Down-regulation of BRCA1 due to mutation occurs in about 3% of breast cancers.[25] Down-regulation of BRCA1 due to methylation of its promoter occurs in about 14% of breast cancers.[26] However, increased expression of miR-182 down-regulates BRCA1 mRNA and protein expression,[27] and increased miR-182 is found in 80% of breast cancers.[28]
In another example, a mutated
To show the frequent ability of microRNAs to alter DNA repair expression, Hatano et al.[30] performed a large screening study, in which 810 microRNAs were transfected into cells that were then subjected to ionizing radiation (IR). For 324 of these microRNAs, DNA repair was reduced (cells were killed more efficiently by IR) after transfection. For a further 75 microRNAs, DNA repair was increased, with less cell death after IR. This indicates that alterations in microRNAs may often down-regulate DNA repair, a likely important early step in progression to cancer.
See also
- Cis-regulatory element
- Glossary of gene expression terms
- RNA interference
References
- ^ )
- PMID 28481885.
- ^ PMID 29034245.
- PMID 24793762.
- ^ a b "Transcriptional Attenuation". www.sci.sdsu.edu. Retrieved 2020-10-11.
- ^ PMID 10613855.
- ^ PMID 19651704.
- ^ "Gene Expression and Regulation | Learn Science at Scitable". www.nature.com. Retrieved 2020-10-12.
- ^ PMID 18955434.
- ^ PMID 21125669.
- S2CID 4430576.
- PMID 22613951.
- ^ PMID 28463381.
- ISBN 978-0-429-09007-3.
- PMID 10744991.
- S2CID 5664103.
- ^ PMID 26294687.
- ISBN 978-0-12-498264-2.
- PMID 15907206.
- S2CID 23518786.
- PMID 16962184.
- ISBN 0-87893-258-5.
- S2CID 25925403.
- PMID 9872332.
- PMID 9042908.
- PMID 10964110.
- PMID 21195000.
- PMID 23249749.
- PMID 25828893.
- PMID 25845598.