CELLULAR IRESES · Mechanism of cellular IRESes translation

The central importance of translation control in cancer is just beginning to be fully appreciated. Translation normally initiates with the recruitment of the initiation factors to the 5’ cap of the mRNA for ribosome binding. Curiously, some normally capped cellular messages, which are involved in cell-cycle control, growth and apoptosis, rely alternatively on an internal ribosome entry site (IRES) at their 5’ end and the 3’ poly(A) tail to support translation. The advantage conferred by the IRES is obvious during shutdown of cap-dependent translation: these mRNAs remain bound to the polysomes and maintain steady expression. The deregulation of such mRNAs is directly implicated in tumorigenesis and clearly links translation to cancer. The precise mechanism of translation via cellular IRES and its regulation, the structural/sequence consensus, and its use remain largely unexplored. Here, using the pro-oncogenic c-myc IRES as model, we propose to investigate the role of the 3’poly(A) tail and the possible involvement of distinct set of regulatory factors for the IRES activity, which does not require the canonical poly(A) tail partner, PABP. We will use innovative functional proteomic approaches, which include capturing the RNP complex formed during ribosomal recruitment, and the establishment of high throughput siRNA-based in vivo and in vitro screening assays. Upon completion of the project, we will have a functional understanding of how the poly(A) tail enhances ribosome recruitment in a non-canonical fashion. These results will enable us to gain insight on mechanistic details of translation control. This research will contribute in EU excellence and competitiveness by covering a key area of basic biological process with a strong interest for Europe for its clear relevance to human diseases. It will raise the potential avenue for novel therapeutic strategies against translation and thus hold great promises to turn the research into useful valuable innovation.