Descripción del proyecto
Consecuencias funcionales de la biogénesis de ribosomas defectuosos
La biogénesis de ribosomas es un proceso complejo estrechamente coordinado con la demanda de ribosomas para garantizar el crecimiento celular. Los ribosomas se generan en pasos clave en los que el ARN ribosómico se ensambla a proteínas ribosómicas. Recientemente, ha quedado clara la conexión entre la biogénesis de ribosomas defectuosos y las enfermedades humanas. Las mutaciones en las proteínas ribosómicas, o factores de biogénesis, aumentan las probabilidades de desarrollar cáncer. Cuando una unidad prerribosómica sufre un error de ensamblaje, la partícula queda retenida en el núcleo. Algunas prepartículas aberrantes escapan a los mecanismos de vigilancia y son exportadas al citoplasma. El proyecto RiboEscapers, financiado con fondos europeos, se propone aplicar un perfilado ribosómico de vanguardia para estudiar las consecuencias funcionales de las mutaciones de las proteínas ribosómicas, que generan ribosomas defectuosos que son exportados al citoplasma (RiboEscapers) y participan activamente en la traducción.
Objetivo
Ribosomes are RNA-protein complexes found in all living cells. Ribosome biogenesis is a complex, cellular process that is tightly coordinated with ribosomes demand to ensure optimal cellular adaptation, growth and proliferation. In eukaryotes, ribosomes are sequentially generated in key steps where the ribosomal RNA (rRNA) is folded, modified, processed, and assembled with ribosomal proteins (r-proteins) to form the two ribosomal subunits. Recently, the connection of defective ribosome biogenesis with human diseases has become clear. This is the case of the so-called ribosomopathies, human syndromes caused by mutations in genes encoding either r-proteins or ribosome biogenesis factors, which are known to increase the probabilities of cancer development. Considering the multi-steps pathway of ribosome biogenesis, the possibilities to introduce errors with possible harmful effects for cell viability are high. In this context, cells have developed multiple surveillance mechanisms to supervise the structural and functional integrity of the ribosome particle. When a preribosomal subunit suffers an assembly error, in most of the cases, the aberrant particle is retained in the nucleus. However, some aberrant pre-particles have been shown to escape the surveillance mechanisms and to be exported to the cytoplasm.
This proposal, aims to explore the functional consequences of r-protein gene mutations, which generate defective ribosomal particles that are successfully exported to the cytoplasm (RiboEscapers) and actively participate in translation in yeast cell. For this purpose, the research action will combine traditional yeast tools together with state-of-the-art methodologies, such ribosome profiling to provide a detailed overview of the r-protein roles in ribosome biogenesis, as well as the consequences of specific defects in this process.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
41004 Sevilla
España