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

我们体内的每个细胞都包含数以千计的分子机器，它们被称为蛋白质。蛋白质在细胞中执行特定的功能。这些蛋白质的编码信息以长四元编码的形式保留在每个细胞的细胞核中，称为脱氧核糖核酸(DNA)。每个细胞都将有专门用于修复环境压力对DNA造成的损伤的蛋白质，专门用于允许细胞复制DNA和许多其他功能的蛋白质。细胞中每种蛋白质的丰度必须受到仔细的调节，以维持细胞的存活和DNA中包含的信息的完整性。通常情况下，癌细胞的蛋白质丰度改变是导致其增殖状态增强的原因。D‘Angiolella实验室研究细胞中蛋白质动态平衡的潜在机制，并专注于这些机制如何在癌症中改变并有助于癌症的发展。对这些过程的了解将有助于开发专门杀死癌细胞的治疗方法，使正常组织保持完好。该实验室在放射治疗后受损DNA修复的基础上，使用遗传筛选来确定蛋白质动态平衡的机制。在目前的提案中，该实验室提议详细研究基因筛查突出的机制。具体地说，这项研究将集中在两种蛋白质上，这两种蛋白质控制着DNA在放射治疗后如何在细胞中被切割，以执行容易出错或无错的DNA修复机制。这些机制之间的平衡对于让细胞在放射治疗引起的许多DNA损伤中存活至关重要。改变癌细胞的这些机制可能有利于细胞死亡和炎症，从而引发抗癌反应。因此，我们的研究将阐明蛋白质动态平衡在保持任何细胞基因组完整性方面的贡献，同时揭示癌症治疗的潜在靶点。

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.