Gene expression is controlled and regulated by nuclear and cytoplasmic surveillance mechanisms in order to preserve the integrity of genetic information. Some of the mechanisms occur in the nucleus during transcription and maturation of mRNAs; they allow recognition and degradation of non-conform mRNAs in the nucleus. Nevertheless, some aberrant mRNAs such as those lacking a Stop codon (Non-Stop mRNA) are exported to the cytoplasm. Because they contain a 5’ cap and a 3’ polyA tail, they are recognized by the translational machinery, engage in translation, but are unlikely to terminate translation properly. Other deleterious features found within mRNAs can interfer with proper translation and lead to stalling of ribosomes (No-Go mRNA). These events lead to elongated or truncated peptides, which may have toxic effect. Cytoplasmic quality control processes recognize ribosomes that are stalled while translating and selectively eliminate the aberrant mRNAs as well as the corresponding aberrant polypeptides to maintain protein homeostasis.
Factors responsible for non-conform mRNAs degradation are relatively well described and involve cytosolic RNA exonucleases in combination with factors that are specific to the different aberrant translation events. The studies of processes targeting nascent polypeptides issued from these aberrant RNAs is, however, much less advanced and, apart form an E3 ubiquitin ligase, Ltn1, described as a ribosome-associated protein involved in the ubiquitinylation of nascent non-conform polypeptides, the factors involved in degradation of the resulting aberrant proteins were unknown when we started this project.
The goal of my team project is to identify factors involved in peptides degradation generated from aberrant mRNA and to understand the mechanism of action of these factors.