Every cell in the body relies on a delicate balance of protein levels to function properly, and cancer cells tip that balance to fuel their own growth. The D'Angiolella laboratory studies how cells regulate protein abundance—a process called protein homeostasis—and how this regulation goes wrong in cancer. Specifically, they focus on two proteins that control how cells repair DNA damage caused by radiation therapy, choosing between error-prone and error-free repair pathways. By altering this choice in cancer cells, the researchers aim to push tumours toward cell death and trigger an immune response, while leaving healthy tissue unharmed. This is fundamental science: it clarifies the basic mechanisms of genome maintenance that operate in every cell. If successful, the work could reveal new molecular targets for drugs that make radiotherapy more effective, potentially improving cancer treatment outcomes without requiring new equipment or complex changes to clinical practice.
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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.
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