Molecular dissection of nutrition-induced ribosome frameshifts, from cancer to aging.

We have recently discovered a novel mechanism by which, in response to low nutrient conditions, most ribosomes experience a -1 ribosome frameshift. This process affects most genes causing a drastic acceleration of mRNA decay and the production of aberrant proteins.

Here we aim to improve our mechanistic understanding of this process using genomic and proteomic methods.First, we will characterize the accumulation of Ct truncated aberrant proteins derived from nutrition-induced frameshift events and their impact on cellular fitness.

As our preliminary data shows that this phenomenon occurs also in cancer cells under amino acid starvation, we will characterize the impact of nutrition-induced frameshift in cancer regulation. We will focus on understanding how frameshift events result in the generation of cancer neoantigens. Preliminary evidence suggest that older cells are more prone to experience nutrition-induced frameshift.

Thus, we will study this using aging models for yeast and humans.

Finally, as the level of nutrition-induced frameshift can be easily modulated, we will pilot the development of novel intervention strategies to increase the expression of neoantigens in cancer cells and minimise proteostasis problems during aging.In essence, our project aims to illuminate a novel layer of gene expression regulation and examine its manipulation for combating cancer and age-related diseases.