7 results on '"Pérez Ortín, José Enrique"'
Search Results
2. Influence of cell volume on the gene transcription rate
- Author
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Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Junta de Andalucía, Chávez, Sebastián [0000-0002-8064-4839], Pérez-Ortín, José Enrique, García-Marcelo, María J., Delgado, Irene, Muñoz-Centeno, Mari Cruz, Chávez, Sebastián, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Junta de Andalucía, Chávez, Sebastián [0000-0002-8064-4839], Pérez-Ortín, José Enrique, García-Marcelo, María J., Delgado, Irene, Muñoz-Centeno, Mari Cruz, and Chávez, Sebastián
- Abstract
Cells vary in volume throughout their life cycle and in many other circumstances, while their genome remains identical. Hence, the RNA production factory must adapt to changing needs, while maintaining the same production lines. This paradox is resolved by different mechanisms in distinct cells and circumstances. RNA polymerases have evolved to cope with the particular circumstances of each case and the different characteristics of the several RNA molecule types, especially their stabilities. Here we review current knowledge on these issues. We focus on the yeast Saccharomyces cerevisiae, where many of the studies have been performed, although we compare and discuss the results obtained in other eukaryotes and propose several ideas and questions to be tested and solved in the future.
- Published
- 2024
3. Enhanced gene regulation by cooperation between mRNA decay and gene transcription
- Author
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Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Junta de Andalucía, García-Martínez, José, Singh, Abhyudai, Medina, Daniel A., Chávez, Sebastián, Pérez-Ortín, José Enrique, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Junta de Andalucía, García-Martínez, José, Singh, Abhyudai, Medina, Daniel A., Chávez, Sebastián, and Pérez-Ortín, José Enrique
- Abstract
It has become increasingly clear in the last few years that gene expression in eukaryotes is not a linear process from mRNA synthesis in the nucleus to translation and degradation in the cytoplasm, but works as a circular one where the mRNA level is controlled by crosstalk between nuclear transcription and cytoplasmic decay pathways. One of the consequences of this crosstalk is the approximately constant level of mRNA. This is called mRNA buffering and happens when transcription and mRNA degradation act at compensatory rates. However, if transcription and mRNA degradation act additively, enhanced gene expression regulation occurs. In this work, we analyzed new and previously published genomic datasets obtained for several yeast mutants related to either transcription or mRNA decay that are not known to play any role in the other process. We show that some, which were presumed only transcription factors (Sfp1) or only decay factors (Puf3, Upf2/3), may represent examples of RNA-binding proteins (RBPs) that make specific crosstalk to enhance the control of the mRNA levels of their target genes by combining additive effects on transcription and mRNA stability. These results were mathematically modeled to see the effects of RBPs when they have positive or negative effects on mRNA synthesis and decay rates. We found that RBPs can be an efficient way to buffer or enhance gene expression responses depending on their respective effects on transcription and mRNA stability.
- Published
- 2023
4. Supporting information for A feedback mechanism controls rDNA copy number evolution in yeast independently of natural selection
- Author
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Arnau, Vicente, Barba-Aliaga, Marina, Singh, Gaurav, Ferri, Javier, García-Martínez, José, Pérez-Ortín, José Enrique, Arnau, Vicente, Barba-Aliaga, Marina, Singh, Gaurav, Ferri, Javier, García-Martínez, José, and Pérez-Ortín, José Enrique
- Published
- 2022
5. A feedback mechanism controls rDNA copy number evolution in yeast independently of natural selection
- Author
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Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Arnau, Vicente, Barba-Aliaga, Marina, Singh, Gaurav, Ferri, Javier, García-Martínez, José, Pérez-Ortín, José Enrique, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Arnau, Vicente, Barba-Aliaga, Marina, Singh, Gaurav, Ferri, Javier, García-Martínez, José, and Pérez-Ortín, José Enrique
- Abstract
Ribosomal DNA (rDNA) is the genetic loci that encodes rRNA in eukaryotes. It is typically arranged as tandem repeats that vary in copy number within the same species. We have recently shown that rDNA repeats copy number in the yeast Saccharomyces cerevisiae is controlled by cell volume via a feedback circuit that senses cell volume by means of the concentration of the free upstream activator factor (UAF). The UAF strongly binds the rDNA gene promoter, but is also able to repress SIR2 deacetylase gene transcription that, in turn, represses rDNA amplification. In this way, the cells with a smaller DNA copy number than what is optimal evolve to increase that copy number until they reach a number that sequestrates free UAF and provokes SIR2 derepression that, in turn, blocks rDNA amplification. Here we propose a mathematical model to show that this evolutionary process can amplify rDNA repeats independently of the selective advantage of yeast cells having bigger or smaller rDNA copy numbers. We test several variants of this process and show that it can explain the observed experimental results independently of natural selection. These results predict that an autoregulated feedback circuit may, in some instances, drive to non Darwinian deterministic evolution for a limited time period.
- Published
- 2022
6. Nucleo-cytoplasmic shuttling of RNA-binding factors: mRNA buffering and beyond
- Author
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Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Junta de Andalucía, Pérez-Ortín, José Enrique, Chávez, Sebastián, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Junta de Andalucía, Pérez-Ortín, José Enrique, and Chávez, Sebastián
- Abstract
Gene expression is a highly regulated process that adapts RNAs and proteins content to the cellular context. Under steady-state conditions, mRNA homeostasis is robustly maintained by tight controls that act on both nuclear transcription and cytoplasmic mRNA stability. In recent years, it has been revealed that several RNA-binding proteins (RBPs) that perform functions in mRNA decay can move to the nucleus and regulate transcription. The RBPs involved in transcription can also travel to the cytoplasm and regulate mRNA degradation and/or translation. The multifaceted functions of these shuttling nucleo-cytoplasm RBPs have raised the possibility that they can act as mRNA metabolism coordinators. In addition, this indicates the existence of crosstalk mechanisms between the enzymatic machineries that drive the different mRNA life-cycle phases. The buffering of the mRNA concentration is the best known consequence of a transcription-degradation crosstalk counteraction, but alternative ways of RBP action can also imply enhanced gene regulation.
- Published
- 2022
7. Functions of the translation factor eIF5A in cellular metabolism and transcriptional control
- Author
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Barba Aliaga, Marina, Alepuz Martínez, Paula, Pérez Ortín, José Enrique, and Departament de Bioquímica i Biologia Molecular
- Subjects
mitochondria ,collagen ,UNESCO::CIENCIAS DE LA VIDA ,translation ,gene expression regulation ,transcription ,metabolism - Abstract
El factor de inicio de traducción de eucariotas 5A (eIF5A) es una proteína esencial y conservada con funciones en las tres fases de la traducción. eIF5A está codificado por dos genes parálogos, TIF51A/TIF51B y EIF5A1/EIF5A2 en levadura y humanos respectivamente. eIF5A es la única proteína que contiene hipusina, una modificación esencial para su actividad, y se une a los ribosomas para facilitar la traducción de motivos con prolinas consecutivas o combinaciones de prolina con glicina y aminoácidos cargados. eIF5A participa en otras funciones y procesos como exporte de mRNAs nucleares, proliferación y apoptosis. Su asociación con enfermades como el cáncer es de interés. En esta tesis se han utilizado los organismos modelo Saccharomyces cerevisiae y Mus Musculus para adquirir conocimiento fundamental de las funciones de eIF5A. Se han identificado dos nuevas dianas de eIF5A para la traducción, una función básica nueva del factor y las bases moleculares de la regulación transcripcional de los dos genes de eIF5A. Nuestros resultados con levadura y células de mamífero demostraron que eIF5A hipusinado es necesario para la síntesis de colágeno I ya que la traducción se para en motivos colagénicos, enriquecidos en prolina y glicina, en deficiencia de eIF5A. Su inactivación redujo el contenido en colágeno I y produjo la retención de colágeno parcialmente sintetizado en el retículo endoplásmico y estrés. La sobreproducción de colágeno I células humanas hepáticas estrelladas tratadas con la citoquina profibrótica TGF-β1 dependía de eIF5A también. En cuanto a la regulación transcripcional de eIF5A, se determinó que la expresión génica de las dos isoformas respondía a las demandas energéticas y dependía de TORC1 y Hap1. En condiciones de respiración, Hap1 activaba TIF51A por unión directa y reprimía TIF51B indirectamente. Por el contrario, cuando la respiración era comprometida, Hap1 se convertía en un represor para inhibir la expresión de TIF51A e inducir TIF51B. Nuestros resultados demostraron el papel esencial de la isoforma Tif51A en la respiración mitocondrial. Se descubrió un nuevo mecanismo que conecta la actividad de eIF5A con las funciones mitocondriales. Se observó que eIF5A es necesario para la traducción de la región de prolinas de Tim50, una proteína esencial que reconoce proteínas mitocondriales y media su importe a la mitocondria. La inactivación de eIF5A inhibía el importe de proteínas y generaba la agregación de precursores y estrés. Finalmente, se reveló una nueva función de eIF5A en la regulación transcripcional de genes cuyos mRNAs lo requieren para la traducción. Nuestros resultados demostraron su unión a la cromatina y su inactivación aumentaba la transcripción de genes que codifican proteínas con motivos dependientes de eIF5A, sugiriendo un efecto transcripcional represor sobre sus dianas. Así, eIF5A no solo funciona en traducción sino también en el control de la síntesis de mRNA para mantener la homeostasis de proteína de sus dianas. The eukaryotic translation initiation factor 5A (eIF5A) is an essential, evolutionarily conserved protein with functions in the three stages of translation. eIF5A is codified by two paralog genes, TIF51A/TIF51B and EIF5A1/EIF5A2 in yeast and human respectively. eIF5A is the only known protein containing hypusine, an essential modification for its activity. eIF5A binds ribosomes to facilitate translation of motifs with consecutive prolines or combinations of proline with glycine and charged amino acids. eIF5A has been linked to other molecular functions and cellular processes such as nuclear mRNA export, proliferation and apoptosis. Its association with the pathogenesis of several diseases including cancer is of interest. In this thesis we have used Saccharomyces cerevisiae and Mus Musculus to gain fundamental knowledge on the functions of eIF5A. Here, we identified and characterized two novel targets requiring eIF5A for translation, a new basic function for the factor and the molecular bases of the transcriptional regulation of the two eIF5A genes. Our results in yeast and mammalian cells proved that hypusinated eIF5A is needed for synthesis of mammalian collagen I as translation stalls at collagenic motifs, enriched in proline and glycine, under eIF5A deficiency. eIF5A inactivation reduced collagen I and led to the retention of partially synthesized collagen I in the endoplasmic reticulum and to stress. The collagen I overproduction in human hepatic stellate cells treated with the profibrotic cytokine TGF-β1 was also dependent on eIF5A. The gene expression regulation of the two isoforms responded to the cellular energy demands and was found to be dependent on TORC1 and Hap1. Under respiratory conditions, Hap1 induced TIF51A through direct binding while indirectly repressed TIF51B. Conversely, when the respiration was compromised, Hap1 became a repressor to down-regulate TIF51A expression and up-regulate TIF51B. Our results demonstrated the essential role of the Tif51A isoform in the mitochondrial respiration. A novel mechanism connecting eIF5A activity with mitochondria functions was revealed. We showed that eIF5A is required for the translation of the proline-rich region of Tim50, an essential protein that specifically recognizes mitochondrial proteins and mediates their import into mitochondria. eIF5A inactivation inhibited mitochondrial protein import and caused precursors to aggregate and stress. Finally, a novel function of eIF5A was uncovered. eIF5A was found to participate in the transcriptional regulation of genes whose mRNAs require eIF5A for translation. Our findings proved the eIF5A binding to chromatin and its absence increases the transcription of specific genes encoding proteins with eIF5A-dependent motifs, suggesting a transcriptional repressor effect on its targets. Thus, our results indicated that eIF5A functions not only in translation but also in the control of mRNA synthesis to maintain protein homeostasis of its targets.
- Published
- 2023
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