The role of E3 ubiquitin ligases in cancer pathogenesis and treatment with Ionising Radiation (IR)

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Each cell in our body contains thousands of molecular machines which are called proteins. Proteins execute dedicated functions in the cells. The information on the coding of such proteins is retained in the form of a long quaternary code in the nuclei of each cell as deoxyribonucleic acid (DNA). Each cell will have proteins dedicated to repair the damage caused by environmental stress to DNA, proteins dedicated to allowing cells to multiply their DNA copy and many other functions. The abundance of each protein in the cell must be carefully regulated to sustain cell survival and the integrity of the information contained in the DNA. Cancer cells have, typically altered protein abundance contributing to their increased proliferation states. The D'Angiolella laboratory studies the mechanisms underlying protein homeostasis in the cells and focuses on how these mechanisms are altered in cancer and contribute to cancer development. The understanding of these processes will help develop treatments to specifically kill the cancer cells leaving the normal tissue intact. The laboratory used genetic screens to identify the mechanisms of protein homeostasis at the basis of the repair of damaged DNA after treatment with radiation therapy. In the current proposal, the laboratory proposes to investigate in detail the mechanisms highlighted by genetic screens. Specifically, the study will focus on two proteins which control how the DNA is cleaved in the cells after radiation treatment to execute error prone or error-free mechanisms of DNA repair. The balance between these mechanisms is crucial to allow cells to survive in the presence of many DNA damaging lesions induced by radiotherapy. Altering these mechanisms in cancer cells could favour cell death and inflammation, eliciting an anti-cancer response. Thus, our studies will clarify the contribution of protein homeostasis in preservation of the genome integrity of any cell and, at the same time, reveal potential targets to exploit for cancer therapy.