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

E3 泛素连接酶在癌症发病机制和电离辐射 (IR) 治疗中的作用

• 批准号: MR/X006980/1
• 负责人: Vincenzo D'Angiolella
• 金额: $ 312.37万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX006980%2F1
• 关键词: role; E3; ubiquitin; ligases; cancer

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.

我们身体的每个细胞都包含成千上万的分子机器，这些分子机器被称为蛋白质。蛋白质在细胞中执行特定的功能。这类蛋白质的编码信息以一长串四元编码的形式保存在每个细胞的细胞核中，即脱氧核糖核酸（DNA）。每个细胞都有专门修复环境压力对DNA造成的损害的蛋白质，这些蛋白质专门允许细胞复制DNA并具有许多其他功能。细胞中每种蛋白质的丰度必须仔细调节，以维持细胞存活和DNA中所含信息的完整性。癌细胞通常具有改变的蛋白质丰度，导致其增殖状态增加。D'Angiolella实验室研究细胞中蛋白质稳态的机制，并关注这些机制如何在癌症中改变并促进癌症的发展。对这些过程的理解将有助于开发特异性杀死癌细胞的治疗方法，使正常组织完好无损。该实验室使用遗传筛选来确定在放射治疗后受损DNA修复的基础上蛋白质稳态的机制。在目前的建议中，实验室建议详细调查基因筛选所强调的机制。具体来说，这项研究将集中在两种蛋白质上，这两种蛋白质控制着辐射治疗后细胞中DNA的切割方式，以执行容易出错或无差错的DNA修复机制。这些机制之间的平衡对于允许细胞在放疗引起的许多DNA损伤病变中存活至关重要。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稳态在保存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。

项目成果

Sequence and structural variations determining the recruitment of WNK kinases to the KLHL3 E3 ligase.

• DOI: 10.1042/bcj20220019
• 发表时间: 2022-03-18
• 期刊: The Biochemical journal

Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation.

• DOI: 10.1038/s41418-022-00983-4
• 发表时间: 2022-10
• 期刊: CELL DEATH AND DIFFERENTIATION
• 影响因子: 12.4
• 作者: Chen, Zhuoyao;Ioris, Rafael M.;Richardson, Stacey;Van Ess, Ava N.;Vendrell, Iolanda;Kessler, Benedikt M.;Buffa, Francesca M.;Busino, Luca;Clifford, Steven C.;Bullock, Alex N.;D'Angiolella, Vincenzo
• 通讯作者: D'Angiolella, Vincenzo

The case of the missing Ks: Base editor screen to assess cellular fitness at single lysines.

• DOI: 10.1016/j.molcel.2023.11.037
• 发表时间: 2023-12
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Varun Gopala Krishna;Verena Gudrun Gautsch;V. D’Angiolella