The p97/VCP system in Ionising Radiation Response

电离辐射响应中的 p97/VCP 系统

• 批准号: MR/X006409/1
• 负责人: Kristijan Ramadan
• 金额: $ 322.65万
• 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%2FX006409%2F1
• 关键词: p97; VCP; system; Ionising; Radiation

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.

保持细胞 DNA 和蛋白质的完整性对于保持健康至关重要。然而，细胞代谢过程、紫外线等外部因素或电离辐射等医疗治疗不断损害我们的 DNA 和蛋白质。如果不加以修复，这种 DNA 损伤可能会导致一系列疾病的发生，包括加速衰老、神经退行性病变和癌症，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，但会上调各种细胞机制以使其生存。其中一个机制是 p97 ATP 酶的上调，p97 ATP 酶是一种参与 DNA 修复和受损蛋白质去除的酶。事实上，已经表明，改变 p97 的功能可以增强各种癌细胞的选择性致死率，并且 p97 抑制剂与电离辐射的结合使用使一些肿瘤对放射更加敏感。尽管这是目前一个有前途的临床研究途径，但癌细胞中 p97 依赖性增加的分子机制仍知之甚少。在将这一概念转化为临床之前，我们必须了解 p97 失活为何会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，这是 DNA 修复和去除受损蛋白质的必需酶，特别关注其在细胞对电离辐射反应中的作用。这是一项基础科学研究项目，具有改善电离放射治疗效果的强大潜力。

项目成果

The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin.

• DOI: 10.1038/s41556-021-00807-6
• 发表时间: 2022-01
• 期刊: Nature cell biology
• 影响因子: 21.3
• 作者: Krastev DB;Li S;Sun Y;Wicks AJ;Hoslett G;Weekes D;Badder LM;Knight EG;Marlow R;Pardo MC;Yu L;Talele TT;Bartek J;Choudhary JS;Pommier Y;Pettitt SJ;Tutt ANJ;Ramadan K;Lord CJ
• 通讯作者: Lord CJ

LARP1 regulates metabolism and mTORC1 activity in cancer

• DOI: 10.1101/2022.09.04.506559
• 发表时间: 2022-09
• 期刊: bioRxiv
• 作者: James Chettle;Z. Dedeic;R. Fischer;I. Vendrell;L. Campo;A. Easton;Molly Browne;Josephine L Morris;Hagen Schwenzer;P. Lascaux;R. Gijsbers;Elisabete Pires;D. Royston;David J. P. Ferguson;A. Coosemans;B. Kessler;J. McCullagh;A. Ahmed;Kristijan Ramadan;M. Bushell;A. Harris;C. Goding;S. Blagden

Atypical K6-ubiquitin chains mobilize p97/VCP and the proteasome to resolve formaldehyde-induced RNA-protein crosslinks

非典型 K6-泛素链动员 p97/VCP 和蛋白酶体来解决甲醛诱导的 RNA-蛋白质交联

• DOI: 10.1016/j.molcel.2023.11.009
• 发表时间: 2023
• 期刊: Molecular Cell
• 影响因子: 16
• 作者: Song W

Isolation and detection of DNA-protein crosslinks in mammalian cells.

• DOI: 10.1093/nar/gkad1178
• 发表时间: 2024-01-25
• 期刊: Nucleic acids research
• 影响因子: 14.9

ATXN3 controls DNA replication and transcription by regulating chromatin structure.

• DOI: 10.1093/nar/gkad212
• 发表时间: 2023-06-23
• 期刊: Nucleic acids research
• 影响因子: 14.9