Review Article - (2022) Volume 8, Issue 1
Received: 28-Dec-2021, Manuscript No. IPBMBJ-21-11335; Editor assigned: 30-Dec-2021, Pre QC No. IPBMBJ-21-11335 (PQ); Reviewed: 13-Jan-2022, QC No. IPBMBJ-21-11335; Revised: 18-Jan-2022, Manuscript No. IPBMBJ-21-11335 (R); Published: 31-Jan-2022, DOI: 10.36648/2471-8084.22.8.51
Mistranslation is the incorporation of errors during translation, which may lead to the mis-incorporation in the polypeptide chain by an altered amino acid that is different from the one being translated by the normal gene. Mistranslation was previously known as the root of disease, but current studies suggest that some organisms have adapted numerous pathways to tolerate the translation error such as fitness can be increased by mistranslation through eradicating deleterious mutations. It can also protect bacteria against oxidative stress. A cell can control mistranslation by different controlling mechanisms. This study discusses different controlling mechanisms used by a cell to control the misincorporation of amino acids. Mistranslation can be controlled by aminoacyl-tRNA synthetase (aaRSs) editing function, discrimination against mis-acylated aminoacyl tRNA (aa-tRNA) by EF-Tu, and by giving up the right substrates for protein synthesis. By manipulating the controlling mechanism of mistranslation, it can be utilized as a tool to produce novel biopharmaceuticals, for curing disease and to enhance the cell potential against environmental stresses.
The maintenance of a specific proteome can be started with a high level of translation control which can be highlighted by the comprehensiveness of the genetic codon. However, a variation between universal genetic codons is especially frequent. The first deviations from the genetic code were recognized in nonsense and frame shifting mutations, and analyses of yeast and human mitochondrial genomes. Standard genetic code can be changed naturally to cause uncertain decoding, codon reassignments, and natural genetic code elongation, such as UAG and UGA stop codons can be decoded with pyro-lysine and selenocysteine [1].
Mistranslation is the incorporation of fault during protein synthesis which can be lead to misinforming of an amino acid that is diverse from being translated by the gene [2]. From all domains of life genetic information must flow from codon to an mRNA and then polypeptide chain [3]. The hereditary sequence is transcribed into mRNA and then translated into protein- peptide are the mechanisms that can abide some errors in these processes. Inaccurate mRNA codon can be produced by incorrectly transcribed DNA sequences; as a result, an unrelated polypeptide chain can be produced by decoding mRNA at the ribosome [4]. Misfolding and shortening of the protein can be done by a fault in central dogma processes which leads to loss of the protein function at a molecular and cellular level by deleterious the essential residue [5,6].
Genetic information flow from DNA sequence to protein sequence is the inexact mechanism. Messenger RNA is transcribed from DNA template and then translated into protein sequence at the ribosome involve a minute level of errors that produced a low level of variable proteins sequence [6]. Aminoacyl-tRNA synthetase has a high level of quality control mechanism that only binds with amino acid-associated tRNA to form aminoacyl- tRNA which is utilized at ribosome for polypeptide synthesis [7]. Impaired aminoacyl-tRNAs are produced by the error in aminoacyl-tRNAs synthetase function that causes inaccurate insertion of amino acid which is not specified by genetic codon through a phenomenon called ‘’mistranslation’’ [2,8]. The loss of protein structural and functional integrity can be linked with the departure from genetic codons that cause phenotypic defects and disease [9].
The expressions of genetic information into functional proteins tolerate some error during these processes. Mistranslation was previously familiar as the root of disease [10,11], but current research showed that certain domains from all life have adapted numerous pathways to tolerate the translation error [12]. However the major cause for these faults is not identified but evidence indicates that the higher rate of mistranslation has a significant role in the protein structure and function [13,14]. The mistranslation error rate can be regulated and differ by environmental situations and organism diversities [9]. Protein translation errors have the adaptive role for understanding by experiment on the wild type of organism and unbiased investigation.
As reported earlier, mistranslation occurs due to the faulty incorporation of amino acids that are dissimilar from the ones coded by the factors. Mistranslation has a big importance in the field of science as it can prove to be worthy because of the effect caused by it.
Mistranslation can be Increased Fitness Levels by Removing Deleterious Mutations
Variance is the basic material for Darwinian evolution, which is produced by mutation in the genetic material during replication and gene expression. The best source for such error is caused by DNA mutations but mainly errors involves during transcription [15-17], tRNA, amino-acylation [18], and expression of mRNA into protein. Protein synthesis is the major possessing error in the central dogma process [15,19,20]. In E. coli, the rate of DNA point mutation could occur at the rate of 104 by the mistranslation rate of 10−5–10−3 per codon [15]. Phenotypic mutations ‘are caused by an error that the ribosome possesses during mistranslation [15,21]. They may involve frameshift mutation or missense mutations [20]. Even though they are not as permanent as DNA mutations, phenotypic mutations have might an impact on evolutionary processes through their erect abundance. Mistranslation is combined with natural selection may have a critical role in the reduction of a protein’s propensity to misfold because the function of protein might be stabilized by natural selection [15,20,22].
Mistranslation can speed up adaptive evolution, as a valuable phenotypic mutation could create a high fitness protein from a low fitness genotypic intermediate. For instance, during the selection of antibiotic resistance, such beneficial phenotypic mutations can increase the activity of an enzyme that deactivates antibiotics. During the appropriate robust selection, even a few high fitness proteins might increase the survival of the population and by the time genetic mutations make the adaptive change permanent, high fitness proteins increase the population time [15,23]. It is unidentified if such ‘stepping stone’ proteins occur in the formation of new protein functions by amino acid changing mutations, while they play role in the production of new protein localization signals via read through mutations [24]. Furthermore, mistranslation can help adaptive evolution by exacerbating the deleterious effects of mutations. As mistranslation enhance the effectiveness of purifying selection [22], it might support removing deleterious mutations from standing genetic variation, consequently rising to mean population fitness.
To inspect how protein mistranslation may influence the evolution of a novel protein function, scientists conducted laboratory based evolution experiments on the antibiotic resistance enzyme TEM-1 β-lactamase. Wild type (‘ancestral’) TEM-1 inactivates β-lactam antibiotics. It is tremendously active against penicillin, such as ampicillin. While it demonstrates insignificant activity on cephalosporins, like cefotaxime, it could develop high activity against them [15,25]. They tentatively created TEM-1 to action on cefotaxime in host cells of E. coli subject to either typical or raised rates of mistranslation and categorized the advanced populaces both genotypically and phenotypically employing high-throughput sequencing. We validate that TEM- 1 populaces progressive in mistake strains inclined towards error are more genotypically diverse and pass on the advantage of fitness to their host. This benefit is linked to the amplified riddance of mutations that can surge mean population fitness under directional selection for a new antibiotic resistance phenotype. When stabilizing selection occurs, mistranslation may diminish rates of mistranslation or increment vagueness to mistranslation [22,26]. In what way impacts of mistranslation interface during directional and stabilizing selection [15] process remain a vital inquiry for upcoming research. For instance, mistranslation may not just have been uncontrolled in initial life forms [15] yet is commonly more successive even at present than hereditary changes, it stays a conceivably vital power in the advancement of present-day proteins. Our perceptions increase the likelihood that mistranslation might infrequently accelerate versatile advancement by purging deleterious changes.
Protein Mistranslation Protects Bacteria against Oxidative Stress
As of late, it has been examined that protein mistranslation can spare microscopic organisms from oxidative stress. Protein mistranslation is versatile and useful under oxidative stress conditions in E. coli. Mistranslated proteins in E. coli activate the general stress reaction and are also the cause of adaptations against serious oxidative stress conditions. Mistranslation most of the time happens in normal E. coli isolates, and is initiated via aminoglycosides, carbon starvation, viral disease, and oxidative stress [27-30].
Mistranslation against Diseases
As of late, it was found that the NPA β-amino methyl-alanine (BMAA) is mistranslated in human tissues at serine (Ser), codons [4,31]. The level of this mistranslation radically diminished by serine supplementation in the media, recommending that the source of this mistranslation might be the competition of non-cognate BMAA with cognate Ser for seryl-tRNA synthetase. There is an expanded risk for neurodegenerative disorders with ingestion of BMAA, for example, Parkinsonism, amyotrophic parallel sclerosis, and Alzheimer’s disease [4,32]. It is an enticing view to utilize nutritional supplementation with similar amino acids as a treatment for maladies, for example, as proteinogenic amino acids production is inexpensive, they are widely accessible over the counter, and are ordinary metabolites for humans. It’s possible that modifying their selectivity of aaRSs by chemicals, initiating changes in amino acid pools, or planned NPA action might be utilized as a part of various strategies to battle numerous maladies with minor side defects for the patient.
Controlling Mechanism of Mistranslations
Protein synthesis has achieved a middle of the road level of loyalty with an error rate of 1 out of 10,000 [19]. There are various repetitive pathways to check precision and accuracy in protein translation. The most imperative include the basic step of tRNA aminoacylation, which joins hereditary data (as the tRNA anticodon) with protein data (as the attached amino acids). Some aaRSs have low error rates inherently, while other aaRSs have an ability that identifies when the inaccurate amino acid is ligated to the tRNA and hydrolyses this bond to take into consideration another round of ligation [2]. Several other quality control systems exist to shield translational mechanism: aminoacyl-tRNA synthetases (aaRSs) proofreading, mismatch tRNA deacylation, EF-Tu discrimination against mis-acylated aminoacyl tRNA (aa-tRNA), legitimate codon-anticodon arrangement in the ribosomal A site, Watson and Crick base pairing of codons and anti-codons at the ribosome, and last but not the least ribosomal proofreading mechanism that was discovered recently [33,34].
The timely synthesis of RNAs can be done by regulating gene expression. Similarly, the proteins that can meet the needs of cells e.g., changing developmental and environmental states, can also be produced. In gene expression, protein synthesis is the final step. It is the step in which the data which is encoded as mRNA is translated into the final product in the form of chains of amino acids which make up the proteins. mRNA which was synthesized should be completely translated so that the cell can take benefit from the gene expression [2,9]. Moreover, translation takes place at a biologically appropriate rate, a cell that splits every 20 minutes gets little advantage from accurate protein synthesis that takes 1 hour to finish. Like higher precision comes with a price like other natural procedures, and through translation rate of protein formation and the speed of mistranslation should be precisely adjusted [2].
Aminoacyl-tRNA Synthetase (aaRSs) Editing Function
Aminoacyl-tRNA synthesis is the initial step of translational mechanism at which error can happen at a significant rate and the part of the aaRSs and their editing function in keeping up translational accuracy is an area of intemperate study [23-28]. A precise choice of amino acid and its binding to the proper tRNA is needed for Aminoacyl-tRNA synthesis. The binding of close related amino acids is prevented by aaRSs through various quality control components of the two step aminoacylation reaction [33,34]. By especially choosing related sets of amino acids and tRNAs during discrimination of close and non-related molecules, aaRSs give a critical initial phase in quality control during translation (Figure 1).
Figure 1: Quality control step during the formation of a cognate amino acid-tRNA pair
Quality control mechanism applied firstly on aminoacyl t-RNA synthetase active site, at this site amino acids were selected. However, twenty naturally occurring amino acids do not show adequate ranges of functional groups functional groups in some may vary by only one (OH- or CH4+ groups) that enables aminoacyl tRNA synthetases to distinguish with accuracy level consistent to a rate of errors ordinarily related with translation, therefore errors may sometimes happen. Such as valine contrast by just one CH4+ group from isoleucine [35]. Escherichia coli and Cerevisiae demonstrated a connection of inaccurate amino acids now and again that can be corrected through editing before transfer or editing after transfer [33].
Editing before a transfer can happen through different mechanisms ranging from non-cognate and labile amino-acyl adenylate class hydrolysis and the non-cognate aa release both are promoted and this editing before transfer may or may not depend on t-RNA [36,37]. Editing after the transfer of amino-acyl t-RNA (non-cognate) needs a CCA tail at 3’ transfer RNA end, that’s connected to aa. When it moves to the editing site from synthesis one, the site where hydrolysis of aa-RNA ester link age occurs. This whole process can happen through direct CCA translocation in cis ones while in trans after aminoacylation release of the active site of t-RNA occur which then leads to rebinding of amino-acyl t-RNA to aminoacyl t-RNA synthetase at the site of editing. Some of the aminoacyl tRNA synthetases likewise compete with EF-Tu (elongation factor Tu) successfully for aminoacyl-transfer RNAs, consequently permitting re-examine of transfer RNA which was mis-acylated and this why got away from the first run of this editing mechanism. That extra layer of aminoacyl transfer RNA synthetase quality control builds decoding accuracy of more than ten times in a protein synthesis system derived from E. coli [38,39]. Editing action after the transfer isn’t restricted to aminoacyl transfer RNA synthetase and includes many trans-acting elements in the trans editing procedure including d-aminoacyl tRNA deacylated [40] (Figure 2).
Figure 2: Quality control steps during the formation of a non-cognate aminoacyl-tRNA
Although the inherent aaRS sites for editing are profoundly saved amongst species the trans-acting elements are significantly more diversified in their structure and distribution, recommending that during evolution specific mechanisms for quality control may have been chosen for more than one time. Such as for the viability of cells, d-aminoacyl-tRNA deacylated are required 3 disconnected groups of transfer RNA deacylated were recognized such as: in microorganism mostly and in eukaryotes d-Tyr-t-RNA deacylated 1 (DTD1), in cyanobacteriaDTD3 and last class named as DTD2 is found mostly in plants and in archaea too [41].
Right Substrate Delivery for Protein Synthesis
After alteration and resembling by aminoacyl transfer RNA synthetase and added trans-acting factors, a ternary complex formed by aminoacyl-tRNAs with eFTu–GTP this complex then binds to the ribosome subsequently [39]. The transfer RNA and aa moieties accomplish contributions related to thermodynamics during elongation factor EF-Tu binding than in result all aminoacyl-transfer RNAs which are cognate binds with the same affinity but aminoacyl-tRNA that are non-cognate binds with affinities that may vary by more than 700 fold [42].
Although eFTu discrimination is not such specific as aminoacyl transfer RNA synthetase editing, it may accommodate added band to the quality control mechanism of translation which can alleviate translation accuracy. Consecutive checkpoints in this mechanism ensure that the aminoacyl-tRNAs are constructed with no error and handed in the aboriginal form to elongation factor Tu and to ribosomes then. Current affirmation proposes that in higher eukaryotes the whole procedure occurs in a single complex which is linked with polysomal ribosomes. Numerous aminoacyl transfer RNA synthetases are well-arranged in multi synthetase complexes of very high molecular weight these high weight molecular complexes also include elongation factors of translation [43]. Now, these multi synthetase complexes by channeling aminoacyl-tRNAs from the aminoacyl transfer RNA Synthetase to elongation factors and then towards the ribosome are contributing toward efficient protein synthesis mechanism [44] (Figure 3).
Figure 3: Formation of a polypeptide in the ribosome
Ribosomal Protein Synthesis
All aminoacyl transfer RNAs apart from initiator aminoacyl tRNAs binds to A site while the latter binds to A site. Hence, the alpha-amino group of aminoacyl transfer RNAs present at the A site reacts with the carbon of the carbonyl group of aminoacyl transfer RNA present at the P site, then a bond is formed known as a peptide bond. Ribosomes are the place where the Synthesis of proteins occurs (Figure 4). In the bacilli and archaea domain, this ample ribonucleoprotein is consists of the 30S and 50S subunit, which forms 70S ribosome, and in the eukaryote domain, it consists of the 40S and 60S subunit, which results in 80S ribosome [45].
Figure 4: Quality control in the ribosome
Ribosomes accommodate three transfer-RNA bindings’ sites: the acceptor (A), the peptidyl (P), and the exit (E) all of these sites participate in translational quality control mechanisms [46].
Transfer RNA that is 1 aa long known as Peptidyl transfer RNA is present on A site while the one that is deacylated, deacylated transfer-RNA is present in P site left to A site. Then 1 codon is translocated by ribosome alone the messenger RNA, that in results move the newly deacylated one into E site known as exit site, peptidyl one to P (peptide) site and A site known as acceptor site is now free to acquire a new incoming amino-acyl t-RNA. The last step of accurate protein synthesis after related aminoacyl transfer RNA transportation to the ribosome acceptor (A) site, is exact m-RNA and t-RNA anti-codon pairing on the peptidyl (P) site a small decoding center On a small ribosomal subunit [47,48].
Proper and improper interactions between codons and anti-codons can be differentiated by ribosomes, but ribosomes cannot find out transfer RNAs that are is acylated. substantial post-transcriptional changes are present in transfer RNA anticodons that during identification of codons can restrict or either extend the wobble effect and hence play an important role in the accuracy and speed of translation [49]. These 7 modifications either provide structural diversities and this codon anti-codon pairing is not all alone sufficient for an account of decoding accuracy which is also accomplished by the ribosomes [2].
It is predicted that if the decoding specificity is gained completely from base pairings of codons and anticodons, then about half of the codons would have been translated with about less than 99 percent perfection, which is far off the error rate of 1 in 103 to 105 codons [50]. There are two step checks for a pairing of codon and anticodons for decoding at the A (acceptor) site, first at the initial selection and the 2nd one at proof reading. At early selection, codon-anticodon pairing is examined, and the ternary complex is made up of amino-acyl-transfer RNA, elongation factor T and GTP bind to the ribosome. Remnants of Ribosome at A site of small (30s) subunit monitors the codon- anticodon helix geometry and this geometry contributes a lot towards ternary complex conformational changes which enhance forward reaction rate of GTP-hydrolysis by the elongation factor Tu [51]. In contrast to this if in codon-anticodon helix mismatch occurs. it does not allow conformational changes to occur that are necessary for fast GTP hydrolysis, hence enhancing the chances that this ternary complex will be dissociated. After this first step of selection hydrolysis of GTP occurred and aminoacyl transfer RNA was released by elongation factor Tu, then this aminoacyl-tRNA either enters Large (the 50S) ribosomal subunit A site or was rejected from the ribosome. If a mismatch occurs in codon-anticodon pairing aminoacyl transfer RNA is probable to be ruled out mostly. This step of translation quality control provides another independent selection step. After the successful binding of amino-acyl transfer RNA at the A-site in the ribosome and contributes towards bond (peptide bond) formation, this newly synthesized peptidyl-transfer RNA is transferred to the P site from the A site.
Ribosomes continuously examine at this stage of translation that codon-anticodon helix does not allow those conformational changes that are necessary for quick GTP hydrolysis, which results in an increased probability of ternary complex separation. GTP is hydrolyzed after this determination step and elongation factor Tu discharge the amino-acyl transfer RNA. This aminoacyl transfer RNA either goes to a larger ribosomal subunit (the 50S) A site or may be rejected by the ribosome, and it is rejected when a mismatch occurs between codon-anticodon interaction. Ribosome at this step of translation check for those mistakes in a codon-anticodons pairing which by chance are missed at amino-acyl transfer RNA charging steps and in proofreading. If the codon-anticodon mismatch is available at the P site it means loss of specificity of the ribosome at A site which results in an intensification of mistakes. This then untimely result in the premature end of the elongation step and peptides are released at an accelerated rate.
The ribosome not only checks codon-anticodon associations in both A and P sites, nevertheless it keeps up the right perusing outline in the messenger RNA to counteract frameshift mutations, which additionally prompt mistranslation and untimely results in termination. Even though the molecular system of maintenance of the reading frame is not crystal clear, both the P and E locales of ribosomes appear to be included in this mechanism. The exit (E) site is particularly vital in the reading- frame maintenance, as both the codon-anticodon connection strength and its occupancy in the exit (E) site specifically add to frame-shift mutations (Table 1).
Table 1: Substrate discrimination mechanism in different steps of translation
| Step in translation | Substrate discriminated | Mechanism of discrimination | Discrimination factor | References studies |
|---|---|---|---|---|
| Aminoacyl-tRNA synthesis | Amino acid | Amino acid recognition | 200–10,000 | 29 |
| Aminoacyl-tRNA synthesis | tRNA | Specific binding of tRNA to the aaRS by nucleic acid recognition | >10,000 | 22 |
| aaRS editing and aaRS resampling | Aminoacyl-tRNA | Amino acid recognition | >10 | 31 |
| EF-Tu binding | Aminoacyl-tRNA | Thermodynamic compensation | Unknown | 46 |
| Initial aminoacyl-tRNA selection | tRNA | A site codon-anticodon pairing | 30–60*‡ | 34 |
| Proofreading and accommodation of aminoacyl-tRNA | tRNA | A site codon-anticodon pairing | 20–100 | 46 |
| Post-peptide bond formation quality control | Peptidyl-tRNA | P site codon-anticodon interaction | >10 | 48 |
| *By experimentally determined rates of catalysis for GTP hydrolysis based on cognate substrates or near-cognate substrates; ‡Presuming equal concentration of cognate substrates & near-cognate substrates. aaRS, aminoacyl | ||||
Need of Quality Control Mechanisms
Quite a bit of our insight into interpretation quality control mechanisms depend on in vitro examines that portray observation at every specific or advanced step of translation. Although this approach has given an abundance of nuclear determination information, extreme little is thought that in what way, where and at what time quality control mechanisms have a part in the cell. It is frequently expected that foremost to keep up the most elevated conceivable level of quality control and the least interpretation mistake rate. Few microorganisms Surely hold stringent quality control components aimed at the synthesis of amino-acyl transfer-RNA. Such as, E. coli phenylalanine separates or discriminates phenylalanine over Tyrosine by a segregation factor of greater than 8,000 to 1 (that means, it mis-incorporates a Tyrosine rather than Phenylalanine just one time per 8,000 duplicates of transfer R-NA Phenylalanine) and furthermore keeps up altering action against Tyrosine-transfer RNA Phenylalanine. Similarly, E. coli and Haemophilus influenzae Proline discriminates Alanine by greater than 3,000 to 1, contains cis altering domain and their editing exercises were additionally expanded by the nearness of the trans-acting cys-tRNA Proline deacylated YbaK [52].
Quality control mechanisms are administered for viability despite their extensive conservation [2,53]. Determination of the selective pressures that lead to the extensive conservation of the quality control mechanisms controlled by aaRSs requires the recognition of all the conditions under which quality control mechanisms are needed for the ideal growth of cells. Lacking the quality control mechanisms not only lead to the wastage of nutrients when mistranslation produces inactive or terminated polypeptides, but it also causes the aggregation of misfolded proteins, some of these improperly folded proteins can produce toxic masses.
In the case quality control mechanism by aaRSs, three different environmental conditions had been selected:
1. Low ratio of cognate amino acids to non-cognate amino acids due to the short supply of nutrients and probably due to other stresses
2. Induction of misfolded protein and heat shock protein response
3. The Stress conditions that result in a decrease in the rate of cell growth, ultimately lessen the appropriate dilution of aggregated and misfolded protein during the growth of cells and permit the buildup of toxic aggregates.
Complications with the Non-Cognate Amino Acids
Quality control mechanism by aaRSs appears to sustain the viability of cells even when there are significant levels of non-cognate amino acids that can enhance tRNA mischarging. aaRSs quality control is required by all the three domains of life when there is an excess of non-cognate and nonstandard amino acids. For instance, mutant AlaRS in the mouse fibroblast cells is-acylates tRNA Ala with amino acid Serine, but the lack of editing pocket for Ser-tRNA. The Sulfolobus solfataricus (Archean) is responsible for the misincorporation of Serine [52,54]. Besides this, in the E. coli cells, mutations in valRS or editing activity of leuRS results in the loss of viability in the occurrence of surplus α-aminobutyrate (nonstandard amino acid) or the non-cognate amino acid Ile. However, the limited knowledge about the occurrence of perturbed amino acids may limit the extraction of possible conclusions from this data [11].
Experiments also propose that the cell response towards altered amino acid ratios may vary when the cells are provided with amino acids either exogenously or manufactured endogenously. For example, the ratio of endogenously synthesized Phe to Tyr decreases up to fourfold due to transferring of yeast from a complex growth medium to minimal growth medium, which results in an increased requirement for PheRS quality control for attaining the optimal growth of cells (N.m.R. and mi., unpublished observations). The pool of amino acids produced endogenously can be affected by the cell stresses like variations in the carbon sources but their consequences on the accuracy of translation are unidentified [2].
Upregulation of Misfolded Proteins Synthesis
Misfolding or unfolding of proteins is crucially associated with environmental conditions. Environmental conditions for instance heat cause the unfolding of protein which effectively harms the growth of cells, and it causes defects in the translational quality control of the cell. The defects caused by mistranslation in the translational quality control mechanism promote the unfolding of proteins. It is found that unfolded protein response, also acknowledged as the heat shock response, is triggered only in the cells that were expressing aaRSs with an editing defect [53]. Moreover, the cells expressing is-acylated aaRSs or aaRSs with an editing defect considerably increase the formation of heat shock proteins as observed in E. coli strains [53]. Purkinje cells with mutated AlaRS, which miscalculates tRNAAla with Ser, showed a significant increase in ubiquitylation and buildup of proteins and boosted production of heat shock protein [10]. The cells of S. cerevisiae were purposely engineered to mistranslate leu amino acid as Ser, this mistranslation resulted from the upregulation of the heat shock proteins synthesis which helped the engineered cells to survive at a lethal temperature of 50°c for a longer period than the wild-type S. cerevisiae cells [55]. Nevertheless, lack of translational quality control may cause mistranslation to occur which results enhance the cell’s capability to survive at lethal temperatures, but it can also cause many growth defects at sub-lethal temperatures because of high levels of misfolded proteins in the cell. The cells of E. coli with an editing defect in IleRS exhibit limited growth of cells at high, but not the lethal temperatures [55].
Effect of Lacking Quality Control Mechanisms on Growth Conditions
Lack of quality control mechanisms by aaRSs may cause some effects in the cells; some of these effects cannot be instantly described that either these are occurring due to surplus non-cognate amino acids or misfolded proteins. However, slow growth is found to be an important aspect that seems to unite these effects. The growth of cells is decelerated by unfavorable environmental conditions, limited supply of cell essential nutrients, and accumulation of toxic masses. The problems exiting in controlling mechanisms can be the leading cause of slow growth in cells by making them more vulnerable to environmental stresses. Such as, E. coli strains to have IleRS with an editing defect were reported as more vulnerable to those antibiotics that can obstruct their ribosomes activity, formation of the cell wall, and DNA replication [55]. Moreover, when these similar cells having IleRS with editing defects were placed on a standard growth medium for several days, a great number of cells with this defect became rifampicin-resistant [56].
Aging bacterial colonies arose with many mutations that cause E. coli cells to develop resistance to rifampicin because these mutations bring favorable changes that support the growth of cells during slow growth situations [57]; this recommends that cells with mutated aaRSs show more severe defects in cell growth than the wild type cells present in the environment. But the significance of aaRSs quality control mechanisms is unidentified under the slow cell growth conditions. Though hair loss and neurodegeneration were observed in mice having mutated AlaRS editing site [10], these side effects may be a result of a buildup of accumulated and ubiquitylated proteins present in the cell, however, this mutation in the AlaRS editing site also results in stimulating the production of unfolded proteins in the Purkinje cells. As if all cells are able of inheriting mutations and therefore, they become susceptible to consequences of misfolded proteins buildup, but the degenerative phenotype is only shown by the Purkinje cells. This effect suggests that some cell-specified physiological variations are required for the translational quality control mechanisms in the cell. In terminally differentiated Purkinje cells, cell division cannot dilute the unfolded protein response which may cause their more rapid accumulation in the cell.
As now we thoroughly understand (at the molecular level) that how the quality control mechanism of mistranslation allows us to understand better that how simple changes in physiological conditions determine mistranslation levels. Such variation in oxidative stress level and also in amino acid pool affects levels of tRNA mischarging and effectiveness of proofreading. In the future, we are needed to develop more and more modified techniques for measuring the rates of mistranslation regularly or to understand this phenomenon precisely that how translational accuracy is affected by external and internal factors. It appears that living beings have advanced a translational fidelity that is finely adjusted and fluctuates as per that specific living being’s natural niche. Genetic code variations impact the cell at the most basic, informational level. These variations provide important regulatory mechanisms, allow cells to increase genetic diversity, and reveal novel tools for synthetic biology applications. Another exciting area for future study can be the tRNA variations’ effect on human biology. It is now evident that mistranslation plays a vital role in both normal development and the pathogenesis of the human disease, thus emphasizing the potential of therapeutics targeting this pathway.
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[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
Citation: Shad M, Malik A, Javid M, Din S, Shakoor S, et al. (2022) Mistranslation of Genetic Codon and Their Controlling Mechanism in Cell. Biochem Mol Bio J. 08:51.
Copyright: Shad M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
