Ribosomal frameshifts as a novel mechanism to control RNA turnover in stress

Descripción del proyecto

Desfases ribosómicos como reguladores del estrés de la reserva de ARNm celular

La modulación de la expresión génica mantiene la homeostasis celular, con procesos de transcripción y degradación de ARN para determinar la abundancia y la composición de la reserva de ARNm. La degradación mediada por mutaciones terminadoras (NMD, siglas de «nonsense-mediated decay») controla la regeneración del ARN, al eliminar las transcripciones erróneas que contienen codones de terminación prematuros (PTC, por sus siglas en inglés). Estudios recientes muestran que los desfases ribosómicos que se producen durante la traducción inducen los PTC e inician la respuesta de NMD. Los datos preliminares sugieren que el estrés regula los desfases ribosómicos y representa un nuevo mecanismo para detectar señales ambientales y regular la abundancia de ARNm. El proyecto financiado con fondos europeos TERMINATOR está investigando la regulación dependiente del estrés de los desfases ribosómicos y su papel en la regeneración del ARN mediante la aplicación de análisis a gran escala en levaduras y células humanas.

Objetivo

Modulation of gene expression is key for maintaining cellular homeostasis in the changing environment. It is achieved through controlling the processes of transcription and RNA degradation that ultimately affect abundance and composition of the mRNA pool. Emerging evidence suggests that the pathways of RNA surveillance and degradation are of paramount importance for fast adaptation of gene expression to stress. One of the most studied mechanisms controlling RNA turnover is nonsense-mediated decay (NMD). It eliminates erroneous transcripts containing premature termination codons (PTC), and also regulates expression of functional transcripts in condition-dependent manner. Recently, my host lab has demonstrated existence of widespread coupling between mRNA decay and translation. This opens a new window for translation dependent regulation of RNA turnover. Specifically, recent studies show that ribosomal frameshifts (RF) occurring during translation induce PTCs and fire NMD response. Preliminary evidence from the host lab suggests that RF is regulated upon stress and could serve as a new mechanism to sense environmental signals and adapt mRNA concentrations. It is yet to be tested if such a regulation is of widespread nature in the cell.
The main goal of this project is to investigate stress-dependent regulation of ribosomal frameshifts and their role in RNA turnover. The 5PSeq approach developed in the host lab will allow for performing high-scale analysis in yeast and human cells, and overcoming existing technological challenges previously limiting research in the field. This project will also explore the cross-talk between RNA turnover and telomere maintenance in cellular response to stress and aging. This will expand the accumulated evidence suggesting interconnection of RNA turnover with other processes involved in cellular adaptability. Finally, I will develop a software package for analysis of RNA degradation datasets that can be used by the research community.