The p97/VCP system in Ionising Radiation Response

保持细胞DNA和蛋白质的完整性对保持健康至关重要。然而，细胞代谢过程、紫外线等外部因素或电离辐射等医学治疗会不断损害我们的DNA和蛋白质。如果不进行修复，这种DNA损伤会导致一系列疾病的发展，包括加速衰老、神经变性和癌症，甚至细胞和有机体死亡。细胞已经进化出专门的DNA修复和蛋白质质量控制机制来检测和修复DNA和蛋白质损伤，从而保护我们免受相关疾病的侵害。癌细胞遭受严重的DNA和蛋白质损伤，但上调各种细胞机制以使其存活。其中一种机制是p97 atp酶的上调，这种酶参与DNA修复和受损蛋白质的去除。事实上，已经有研究表明，改变p97的功能可以增强各种癌细胞的选择性致死率，并且使用p97抑制剂与电离辐射相结合会使某些肿瘤对辐射更敏感。尽管目前这是一个很有前途的临床研究途径，但癌细胞中这些p97依赖性增加的分子机制仍然知之甚少。在将这一概念应用于临床之前，我们必须了解p97失活导致放射敏感性和癌细胞死亡的分子细节。因此，我们的目标是进一步研究p97 atp酶，DNA修复和去除受损蛋白的必需酶，特别关注其在细胞对电离辐射的反应中的作用。这是一项基础科学研究计划，在改善电离放射治疗的结果方面具有很大的潜力。

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.