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

Descrizione del progetto

Gli slittamenti di fase ribosomiali come regolatori dello stress del pool di mRNA cellulare

La modulazione dell’espressione genica mantiene l’omeostasi cellulare, implicando processi di trascrizione e di decomposizione di RNA per stabilire la ricchezza e la composizione del pool di mRNA. Il decadimento mediato da un nonsenso controlla la variazione dell’RNA, eliminando trascrizioni errate che contengono codoni di terminazione prematuri. Studi recenti hanno mostrato che gli slittamenti di fase ribosomiali, che avvengono durante la traslazione, inducono tali codoni e innescano la risposta legata al decadimento mediato da un nonsenso. Dati preliminari indicano che lo stress regola gli slittamenti di fase ribosomiali e che rappresenta un nuovo meccanismo per percepire i segnali ambientali e regolare l’abbondanza dell’mRNA. Il progetto TERMINATOR, finanziato dall’UE, sta analizzano la regolazione dipendente dallo stress degli slittamenti di fase ribosomiali e del loro ruolo nella variazione dell’RNA, applicando analisi su larga scala in lieviti e in cellule umane.

Obiettivo

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.