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1.
BMC Ecol Evol ; 24(1): 36, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38494489

RESUMO

BACKGROUND: Sequence variation produced by mutation provides the ultimate source of natural selection for species adaptation. Unlike nonsynonymous mutation, synonymous mutations are generally considered to be selectively neutral but accumulating evidence suggests they also contribute to species adaptation by regulating the flow of genetic information and the development of functional traits. In this study, we analysed sequence characteristics of ATP6, a housekeeping gene from 139 Phytophthora infestans isolates, and compared the fitness components including metabolic rate, temperature sensitivity, aggressiveness, and fungicide tolerance among synonymous mutations. RESULTS: We found that the housekeeping gene exhibited low genetic variation and was represented by two major synonymous mutants at similar frequency (0.496 and 0.468, respectively). The two synonymous mutants were generated by a single nucleotide substitution but differed significantly in fitness as well as temperature-mediated spatial distribution and expression. The synonymous mutant ending in AT was more common in cold regions and was more expressed at lower experimental temperature than the synonymous mutant ending in GC and vice versa. CONCLUSION: Our results are consistent with the argument that synonymous mutations can modulate the adaptive evolution of species including pathogens and have important implications for sustainable disease management, especially under climate change.


Assuntos
Fungicidas Industriais , Phytophthora infestans , Mutação Silenciosa , Phytophthora infestans/genética , Mutação/genética , Seleção Genética
2.
J Mol Biol ; 436(6): 168487, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38341172

RESUMO

Synonymous mutations in messenger RNAs (mRNAs) can reduce protein-protein binding substantially without changing the protein's amino acid sequence. Here, we use coarse-grain simulations of protein synthesis, post-translational dynamics, and dimerization to understand how synonymous mutations can influence the dimerization of two E. coli homodimers, oligoribonuclease and ribonuclease T. We synthesize each protein from its wildtype, fastest- and slowest-translating synonymous mRNAs in silico and calculate the ensemble-averaged interaction energy between the resulting dimers. We find synonymous mutations alter oligoribonuclease's dimer properties. Relative to wildtype, the dimer interaction energy becomes 4% and 10% stronger, respectively, when translated from its fastest- and slowest-translating mRNAs. Ribonuclease T dimerization, however, is insensitive to synonymous mutations. The structural and kinetic origin of these changes are misfolded states containing non-covalent lasso-entanglements, many of which structurally perturb the dimer interface, and whose probability of occurrence depends on translation speed. These entangled states are kinetic traps that persist for long time scales. Entanglements cause altered dimerization energies for oligoribonuclease, as there is a large association (odds ratio: 52) between the co-occurrence of non-native self-entanglements and weak-binding dimer conformations. Simulated at all-atom resolution, these entangled structures persist for long timescales, indicating the conclusions are independent of model resolution. Finally, we show that regions of the protein we predict to have changes in entanglement are also structurally perturbed during refolding, as detected by limited-proteolysis mass spectrometry. Thus, non-native changes in entanglement at dimer interfaces is a mechanism through which oligomer structure and stability can be altered.


Assuntos
Membrana Celular , Escherichia coli , Exorribonucleases , Multimerização Proteica , Mutação Silenciosa , Escherichia coli/enzimologia , Exorribonucleases/química , Exorribonucleases/genética , Cinética , Dobramento de Proteína , Multimerização Proteica/genética , Membrana Celular/enzimologia
3.
Biomolecules ; 14(1)2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-38275761

RESUMO

Synonymous mutations result from the degeneracy of the genetic code. Most amino acids are encoded by two or more codons, and mutations that change a codon to another synonymous codon do not change the amino acid in the gene product. Historically, such mutations have been considered silent because they were assumed to have no to very little impact. However, research in the last few decades has produced several examples where synonymous mutations play important roles. These include optimizing expression by enhancing translation initiation and accelerating or decelerating translation elongation via codon usage and mRNA secondary structures, stabilizing mRNA molecules and preventing their breakdown before translation, and faulty protein folding or increased degradation due to enhanced ubiquitination and suboptimal secretion of proteins into the appropriate cell compartments. Some consequences of synonymous mutations, such as mRNA stability, can lead to different outcomes in prokaryotes and eukaryotes. Despite these examples, the significance of synonymous mutations in evolution and in causing disease in comparison to nonsynonymous mutations that do change amino acid residues in proteins remains controversial. Whether the molecular mechanisms described by which synonymous mutations affect organisms can be generalized remains poorly understood and warrants future research in this area.


Assuntos
Biossíntese de Proteínas , Mutação Silenciosa , Códon/genética , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , Proteínas/genética , Aminoácidos/genética , Evolução Molecular
4.
Br J Haematol ; 204(2): 399-401, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37985143

RESUMO

The genetic underpinnings of beta-thalassaemia encompass a myriad of molecular mechanisms. The ability of synonymous mutations, an often-overlooked category of variants, to influence ß-globin expression and phenotypic disease is highlighted by this report by Gorivale et al. Commentary on: Gorivale et al. When a synonymous mutation breaks the silence in a thalassaemia patient. Br J Haematol 2024;204:677-682.


Assuntos
Talassemia , Talassemia beta , Humanos , Mutação Silenciosa , Mutação , Talassemia beta/genética , Globinas beta/genética , Globinas/genética
5.
Br J Haematol ; 204(2): 677-682, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37742714

RESUMO

Synonymous mutations were considered to lack functional roles in human diseases; however, distinguishing deleterious synonymous mutations from benign ones is still a challenge. In this article, we identified a deleterious synonymous mutation ß-codon 16 (C>T). HBB: c.51C>T, in compound heterozygous form with known ß-thalassaemia mutation patients who clinically presented as non-transfusion-dependent thalassaemia (NTDT). A total of 9 families with 11 compound heterozygous index cases were reported. In the heterozygous state, codon 16 (C>T) mutation results in borderline HbA2 (3.18 ± 0.36%) and slightly reduced RBC indices (RBCs: 4.73 ± 0.75 × 106 /µL, Hb: 12.26 ± 2.60 g/dL, MCV: 79.48 ± 8.40 fL, MCH: 25.95 ± 4.15 pg). The compound heterozygous patients showed elevated HbA2 (5.98 ± 1.17%) and HbF (12.75 ± 7.51%) and presented clinically as NTDT with a mean Hb of 6.95 ± 1.29 g/dL. Many of them were dependent on few transfusions and had mild splenomegaly. Of the 11 patients, 5 (45.4%) were treated with hydroxyurea. This study highlights the clinical significance of synonymous mutation, when inherited with other ß-thalassaemia mutations leading to the phenotype of NTDT. Thus, the study would help to improve screening protocols for ß-thalassaemia carriers, which will ultimately improve the prevention programme.


Assuntos
Talassemia , Talassemia beta , Humanos , Talassemia beta/genética , Mutação Silenciosa , Eritrócitos , Mutação , Códon
6.
IEEE J Biomed Health Inform ; 28(2): 1144-1151, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38096097

RESUMO

Accurate identification of driver mutations is crucial in genetic studies of human cancers. While numerous cancer driver missense mutations have been identified, research into potential cancer drivers for synonymous mutations has shown limited success to date. Here, we developed a novel machine learning framework, epSMic, for predicting cancer driver synonymous mutations. epSMic employs an iterative feature representation scheme that facilitates the learning of discriminative features from various sequential models in a supervised iterative mode. We constructed the benchmark datasets and encoded the embedding sequence, physicochemical property, and basic information such as conservation and splicing feature. The evaluation results on benchmark test datasets demonstrate that epSMic outperforms existing methods, making it a valuable tool for researchers in identifying functional synonymous mutations in cancer. We hope epSMic can enable researchers to concentrate on synonymous mutations that have a functional impact on cancer.


Assuntos
Neoplasias , Mutação Silenciosa , Humanos , Neoplasias/genética , Aprendizado de Máquina
7.
BMC Bioinformatics ; 24(1): 462, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-38062391

RESUMO

BACKGROUND: Synonymous mutations, which change the DNA sequence but not the encoded protein sequence, can affect protein structure and function, mRNA maturation, and mRNA half-lives. The possibility that synonymous mutations might be enriched in cancer has been explored in several recent studies. However, none of these studies control for all three types of mutational heterogeneity (patient, histology, and gene) that are known to affect the accurate identification of non-synonymous cancer-associated genes. Our goal is to adopt the current standard for non-synonymous mutations in an investigation of synonymous mutations. RESULTS: Here, we create an algorithm, MutSigCVsyn, an adaptation of MutSigCV, to identify cancer-associated genes that are enriched for synonymous mutations based on a non-coding background model that takes into account the mutational heterogeneity across these levels. Using MutSigCVsyn, we first analyzed 2572 cancer whole-genome samples from the Pan-cancer Analysis of Whole Genomes (PCAWG) to identify non-synonymous cancer drivers as a quality control. Indicative of the algorithm accuracy we find that 58.6% of these candidate genes were also found in Cancer Census Gene (CGC) list, and 66.2% were found within the PCAWG cancer driver list. We then applied it to identify 30 putative cancer-associated genes that are enriched for synonymous mutations within the same samples. One of the promising gene candidates is the B cell lymphoma 2 (BCL-2) gene. BCL-2 regulates apoptosis by antagonizing the action of proapoptotic BCL-2 family member proteins. The synonymous mutations in BCL2 are enriched in its anti-apoptotic domain and likely play a role in cancer cell proliferation. CONCLUSION: Our study introduces MutSigCVsyn, an algorithm that accounts for mutational heterogeneity at patient, histology, and gene levels, to identify cancer-associated genes that are enriched for synonymous mutations using whole genome sequencing data. We identified 30 putative candidate genes that will benefit from future experimental studies on the role of synonymous mutations in cancer biology.


Assuntos
Neoplasias , Mutação Silenciosa , Humanos , Genoma Humano , Mutação , Neoplasias/patologia , RNA Mensageiro , Proteínas Proto-Oncogênicas c-bcl-2 , Análise Mutacional de DNA
8.
BMC Genomics ; 24(1): 732, 2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-38049728

RESUMO

BACKGROUND: Single synonymous codon mutations typically have only minor or no effects on gene function. Here, we estimate the effects on cell growth of ~ 200 single synonymous codon mutations in an operonic context by mutating almost all positions of ccdB, the 101-residue long cytotoxin of the ccdAB Toxin-Antitoxin (TA) operon to most degenerate codons. Phenotypes were assayed by transforming the mutant library into CcdB sensitive and resistant E. coli strains, isolating plasmid pools, and subjecting them to deep sequencing. Since autoregulation is a hallmark of TA operons, phenotypes obtained for ccdB synonymous mutants after transformation in a RelE toxin reporter strain followed by deep sequencing provided information on the amount of CcdAB complex formed. RESULTS: Synonymous mutations in the N-terminal region involved in translation initiation showed the strongest non-neutral phenotypic effects. We observe an interplay of numerous factors, namely, location of the codon, codon usage, t-RNA abundance, formation of anti-Shine Dalgarno sequences, predicted transcript secondary structure, and evolutionary conservation in determining phenotypic effects of ccdB synonymous mutations. Incorporation of an N-terminal, hyperactive synonymous mutation, in the background of the single synonymous codon mutant library sufficiently increased translation initiation, such that mutational effects on either folding or termination of translation became more apparent. Introduction of putative pause sites not only affects the translational rate, but might also alter the folding kinetics of the protein in vivo. CONCLUSION: In summary, the study provides novel insights into diverse mechanisms by which synonymous mutations modulate gene function. This information is useful in optimizing heterologous gene expression in E. coli and understanding the molecular bases for alteration in gene expression that arise due to synonymous mutations.


Assuntos
Proteínas de Escherichia coli , Escherichia coli , Biossíntese de Proteínas , Mutação Silenciosa , Códon , Escherichia coli/genética , Fenótipo , Proteínas de Escherichia coli/genética
9.
Immun Inflamm Dis ; 11(10): e1049, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37904676

RESUMO

BACKGROUND: X-linked agammaglobulinemia (XLA) is the most common form of agammaglobulinemia and is caused by mutations in Btk, which encodes Bruton tyrosine kinase (BTK). CASE DESCRIPTION: We describe a 36-year-old male who presented as an infant with hypogammaglobulinemia and sinopulmonary infections and was initially diagnosed with common variable immunodeficiency. Genetic testing showed he was hemizygous for Btk c.240G > A. This synonymous variant affecting the last nucleotide of exon 3 leads to aberrant splicing of most but not all mRNA transcripts. CONCLUSION: We demonstrated reduced BTK protein expression confirming the pathogenicity of the variant and related our findings to genotype-phenotype relationship studies ina XLA caused by synonymous mutations.


Assuntos
Agamaglobulinemia , Masculino , Lactente , Humanos , Adulto , Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Proteínas Tirosina Quinases/genética , Mutação Silenciosa
10.
mBio ; 14(5): e0084123, 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37787543

RESUMO

IMPORTANCE: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, one of the deadliest infectious diseases worldwide. Previous studies have established that synonymous recoding to introduce rare codon pairings can attenuate viral pathogens. We hypothesized that non-optimal codon pairing could be an effective strategy for attenuating gene expression to create a live vaccine for Mtb. We instead discovered that these synonymous changes enabled the transcription of functional mRNA that initiated in the middle of the open reading frame and from which many smaller protein products were expressed. To our knowledge, this is one of the first reports that synonymous recoding of a gene in any organism can create or induce intragenic transcription start sites.


Assuntos
Mycobacterium , Mutação Silenciosa , Códon , RNA Mensageiro , Mycobacterium/genética
11.
Int J Mol Sci ; 24(13)2023 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-37445732

RESUMO

Synonymous variants, traditionally regarded as silent mutations due to their lack of impact on protein sequence, structure and function, have been the subject of increasing scrutiny. This commentary explores the emerging evidence challenging the notion of synonymous variants as functionally inert. Analysis of the activity of 70 synonymous variants in the HIV Tat transcription factor revealed that 50% of the variants exhibited significant deviations from wild-type activity. Our analysis supports previous work and raises important questions about the broader impact of non-silent synonymous variants in human genes. Considering the potential functional implications, the authors propose classifying such variants as "synonymous variants of uncertain silence" (sVUS), highlighting the need for cautious interpretation and further investigations in clinical and genetic testing settings.


Assuntos
Mutação Silenciosa , Fatores de Transcrição , Humanos , Regulação da Expressão Gênica
12.
World J Pediatr ; 19(7): 687-700, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37154862

RESUMO

BACKGROUND: Adenosine deaminase (ADA) is a key enzyme in the purine salvage pathway. Genetic defects of the ADA gene can cause a subtype of severe combined immunodeficiency. To date, few Chinese cases have been reported. METHODS: We retrospectively reviewed the medical records of patients diagnosed with ADA deficiency in Beijing Children's Hospital and summarized the previously published ADA deficiency cases from China in the literature. RESULTS: Nine patients were identified with two novel mutations (W272X and Q202 =). Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations of Chinese ADA-deficient patients. The ADA genotype has a major effect on the clinical phenotype. Notably, a novel synonymous mutation (c.606G>A, p.Q202=) was identified in a delayed-onset patient, which affected pre-mRNA splicing leading to a frameshift and premature truncation of the protein. Furthermore, the patient showed γδT cells expansion with an increased effect or phenotype, which may be associated with the delayed onset of disease. In addition, we reported cerebral aneurysm and intracranial artery stenosis for the first time in ADA deficiency. Five patients died with a median age of four months, while two patients received stem cell transplantation and are alive. CONCLUSIONS: This study described the first case series of Chinese ADA-deficient patients. Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations in our patients. We identified a synonymous mutation that affected pre-mRNA splicing in the ADA gene, which had never been reported in ADA deficiency. Furthermore, we reported cerebral aneurysm in a delayed-onset patient for the first time. Further study is warranted to investigate the underlying mechanisms.


Assuntos
Aneurisma Intracraniano , Imunodeficiência Combinada Severa , Humanos , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Insuficiência de Crescimento , Mutação , Estudos Retrospectivos , Precursores de RNA , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Mutação Silenciosa , Lactente
13.
Sci Rep ; 13(1): 7593, 2023 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-37165041

RESUMO

Recent studies have shown that some silent mutations can be harmful to various processes. In this study, we performed a comprehensive in silico analysis to elucidate the effects of silent mutations on cancer pathogenesis using exome sequencing data derived from the Cancer Genome Atlas. We focused on the codon optimality scores of silent mutations, which were defined as the difference between the optimality of synonymous codons, calculated using the codon usage table. The relationship between cancer evolution and silent mutations showed that the codon optimality score of the mutations that occurred later in carcinogenesis was significantly higher than of those that occurred earlier. In addition, mutations with higher scores were enriched in genes involved in the cell cycle and cell division, while those with lower scores were enriched in genes involved in apoptosis and cellular senescence. Our results demonstrate that some silent mutations can be involved in cancer pathogenesis.


Assuntos
Neoplasias , Mutação Silenciosa , Humanos , Evolução Molecular , Mutação , Códon , Neoplasias/genética
14.
PLoS One ; 18(4): e0283985, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37098020

RESUMO

BACKGROUND: Variation in genes involved in ethanol metabolism has been shown to influence risk for alcohol dependence (AD) including protective loss of function alleles in ethanol metabolizing genes. We therefore hypothesized that people with severe AD would exhibit different patterns of rare functional variation in genes with strong prior evidence for influencing ethanol metabolism and response when compared to genes not meeting these criteria. OBJECTIVE: Leverage a novel case only design and Whole Exome Sequencing (WES) of severe AD cases from the island of Ireland to quantify differences in functional variation between genes associated with ethanol metabolism and/or response and their matched control genes. METHODS: First, three sets of ethanol related genes were identified including those a) involved in alcohol metabolism in humans b) showing altered expression in mouse brain after alcohol exposure, and altering ethanol behavioral responses in invertebrate models. These genes of interest (GOI) sets were matched to control gene sets using multivariate hierarchical clustering of gene-level summary features from gnomAD. Using WES data from 190 individuals with severe AD, GOI were compared to matched control genes using logistic regression to detect aggregate differences in abundance of loss of function, missense, and synonymous variants, respectively. RESULTS: Three non-independent sets of 10, 117, and 359 genes were queried against control gene sets of 139, 1522, and 3360 matched genes, respectively. Significant differences were not detected in the number of functional variants in the primary set of ethanol-metabolizing genes. In both the mouse expression and invertebrate sets, we observed an increased number of synonymous variants in GOI over matched control genes. Post-hoc simulations showed the estimated effects sizes observed are unlikely to be under-estimated. CONCLUSION: The proposed method demonstrates a computationally viable and statistically appropriate approach for genetic analysis of case-only data for hypothesized gene sets supported by empirical evidence.


Assuntos
Alcoolismo , Humanos , Camundongos , Animais , Alcoolismo/genética , Alcoolismo/diagnóstico , Exoma/genética , Alelos , Etanol , Mutação Silenciosa , Variação Genética
16.
J Basic Microbiol ; 63(5): 530-541, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37032321

RESUMO

Salmonella enterica contamination is a primary cause of global food poisoning. Using phages as bactericidal alternatives to antibiotics could confront the issue of drug resistance. However, the problem of phage resistance, especially mutant strains with multiple phage resistance, is a critical barrier to the practical application of phages. In this study, a library of EZ-Tn5 transposable mutants of susceptible host S. enterica B3-6 was constructed. After the infestation pressure of a broad-spectrum phage TP1, a mutant strain with resistance to eight phages was obtained. Analysis of the genome resequencing results revealed that the SefR gene was disrupted in the mutant strain. The mutant strain displayed a reduced adsorption rate of 42% and a significant decrease in swimming and swarming motility, as well as a significantly reduced expression of the flagellar-related FliL and FliO genes to 17% and 36%, respectively. An uninterrupted form of the SefR gene was cloned into vector pET-21a (+) and used for complementation of the mutant strain. The complemented mutant exhibited similar adsorption and motility as the wild-type control. These results suggest that the disrupted flagellar-mediated SefR gene causes an adsorption inhibition, which is responsible for the phage-resistant phenotype of the S. enterica transposition mutant.


Assuntos
Bacteriófagos , Salmonella enterica , Mutação Silenciosa , Mutação , Antibacterianos/farmacologia
17.
Int J Biol Macromol ; 235: 123835, 2023 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-36870640

RESUMO

Although synonymous mutations have long been thought to lack striking results, a growing body of research shows these mutations have highly variable effects. In this study, the impact of synonymous mutations in the development of thermostable luciferase was investigated using a combination of experimental and theoretical approaches. Using bioinformatics analysis, the codon usage features in the Lampyridae family's luciferases were studied and four synonymous mutations of Arg in luciferase were created. An exciting result was that the analysis of kinetic parameters showed a slight increase in the thermal stability of the mutant luciferase. AutoDock Vina, %MinMax algorithm, and UNAFold Server were used to perform molecular docking, folding rate, and RNA folding, respectively. Here, it was assumed that in the region (Arg337) with a moderate propensity for coil, synonymous mutation altered the rate of translation, which in turn may lead to a slight change in the structure of the enzyme. According to the molecular dynamics simulation data, local minor global flexibility is observed in the context of the protein conformation. A plausible explanation is that this flexibility may strengthen hydrophobic interactions due to its sensitivity to a molecular collision. Accordingly, thermostability originated mainly from hydrophobic interaction.


Assuntos
Simulação de Dinâmica Molecular , Mutação Silenciosa , Simulação de Acoplamento Molecular , Luciferases de Vaga-Lume/metabolismo , Dobramento de RNA
18.
Genomics ; 115(3): 110603, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36893872

RESUMO

The genetic code has degenerate codons that produce no change in the translated protein sequence and are generally thought to be silent. However, some synonymous variants are clearly not silent. Herein, we questioned the frequency of non-silent synonymous variants. We tested how random synonymous variants in the HIV Tat transcription factor effect transcription of an LTR-GFP reporter. Our model system has the advantage of directly measuring the function of the gene in human cells. Approximately, 67% of synonymous variants in Tat were non-silent, either having reduced activity or were full loss-of-function alleles. Eight mutant codons had higher codon usage than wild type, accompanied by reduced transcriptional activity. These were clustered on a loop in the Tat structure. We conclude that most synonymous Tat variants are not silent in human cells, and 25% are associated with changes in codon usage, likely effecting protein folding.


Assuntos
Uso do Códon , Infecções por HIV , Humanos , Alelos , Códon , Mutação Silenciosa , Infecções por HIV/genética
19.
Mol Oncol ; 17(7): 1302-1323, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36808875

RESUMO

Oestrogen receptor-alpha (ERα) positivity is intimately associated with the development of hormone-dependent breast cancers. A major challenge in the treatment of these cancers is to understand and overcome the mechanisms of endocrine resistance. Recently, two distinct translation programmes using specific transfer RNA (tRNA) repertoires and codon usage frequencies were evidenced during cell proliferation and differentiation. Considering the phenotype switch of cancer cells to more proliferating and less-differentiated states, we can speculate that the changes in the tRNA pool and codon usage that likely occur make the ERα coding sequence no longer adapted, impacting translational rate, co-translational folding and the resulting functional properties of the protein. To verify this hypothesis, we generated an ERα synonymous coding sequence whose codon usage was optimized to the frequencies observed in genes expressed specifically in proliferating cells and then investigated the functional properties of the encoded receptor. We demonstrate that such a codon adaptation restores ERα activities to levels observed in differentiated cells, including: (a) an enhanced contribution exerted by transactivation function 1 (AF1) in ERα transcriptional activity; (b) enhanced interactions with nuclear receptor corepressor 1 and 2 [NCoR1 and NCoR2 (also known as SMRT) respectively], promoting repressive capability; and (c) reduced interactions with SRC proto-oncogene, non-receptor tyrosine kinase (Src) and phosphoinositide 3-kinase (PI3K) p85 kinases, inhibiting MAPK and AKT signalling pathway.


Assuntos
Neoplasias , Receptores de Estrogênio , Receptores de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Mutação Silenciosa , Linhagem Celular Tumoral , Códon/genética , Neoplasias/genética
20.
Nat Rev Microbiol ; 21(4): 221, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36781959
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