A single enzyme, p97, helps cancer cells survive the DNA damage caused by radiotherapy, and researchers want to understand exactly how it does that. All cells have repair systems that fix broken DNA and remove damaged proteins. Cancer cells, which suffer constant genetic chaos, rely heavily on these systems to stay alive. They often ramp up production of p97, an enzyme that works in both DNA repair and protein cleanup. Early studies show that blocking p97 makes some tumours more sensitive to radiation, but the molecular details of why this happens remain unknown. This is fundamental science. The team will map the precise role of p97 in how cells respond to ionising radiation, identifying the specific repair pathways it controls and how its inactivation triggers cancer cell death. Without this mechanistic understanding, combining p97 inhibitors with radiotherapy remains a blind shot. If the work succeeds, it could provide a rational basis for designing combination therapies that selectively kill cancer cells while sparing healthy tissue. Past fundamental discoveries about DNA repair enzymes have directly led to drugs like PARP inhibitors, now standard treatments for certain cancers. A deeper grasp of p97 could follow a similar path from lab bench to clinic.
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Maintaining the integrity of our cells' DNA and proteins is essential to remain healthy. However, cellular metabolic processes, external factors like UV or medical treatments like ionizing radiation constantly damage our DNA and proteins. If not repaired, such DNA damage can lead to the development of a range of diseases including accelerated ageing, neurodegeneration and cancer or even cell and organismal death. Cells have evolved specialised DNA repair and protein quality control mechanisms to detect and repair DNA and protein damage and thus protect us from the associated diseases. Cancer cells suffer from severe DNA and protein damage but upregulate various cellular mechanisms to allow their survival. One of these mechanisms is upregulation of p97 ATPase, an enzyme that is involved in both DNA repair and removal of damaged proteins. Indeed, it has been shown that altering the functions of p97 enhances selective lethality of various cancer cells, and that the use of p97 inhibitors combined with ionising radiation renders some tumours more radiosensitive. Although this is currently a promising clinical research avenue, the molecular mechanisms underlying these p97 increased dependencies in cancer cells remain poorly understood. Before translating this concept into the clinic, we have to understand the molecular details of why p97 inactivation causes radiosensitivity and cancer cell death. Therefore, we aim to further study p97 ATPase, the essential enzyme in DNA repair and removal of damaged proteins, with the special focus on its role in cellular response to ionizing radiation. This is a basic science research programme that has a strong potential to improve the outcome of ionizing radiation therapy.
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