Gene expression is controlled and regulated by nuclear and cytoplasmic surveillance mechanisms in order to preserve the integrity of genetic information. Nuclear mechanisms occur 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 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, engaged in translation but are unlikely to terminate translation. Other mRNA containing more tenuous particularity can be engaged in translation but result in stalled 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 generated to maintain protein homeostasis.
The factors responsible for the degradation of the non-conform mRNAs 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 the processes targeting the 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 the degradation of the resulting aberrant proteins are still unknown
The goal of the team project is to identify factors involved in the degradation of peptides issues from aberrant mRNA and to understand the mechanism of action of these factors.