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不断损害我们的DNA和蛋白质。如果不修复，这种DNA损伤可能导致一系列疾病的发展，包括加速老化，神经退行性变和癌症，甚至细胞和生物体死亡。细胞已经进化出专门的DNA修复和蛋白质质量控制机制，以检测和修复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。这些机制之一是p97 ATP酶的上调，这是一种参与DNA修复和去除受损蛋白质的酶。事实上，已经证明改变p97的功能可以增强各种癌细胞的选择性杀伤力，并且p97抑制剂与电离辐射结合使用会使一些肿瘤对辐射更敏感。虽然这是目前一个有前途的临床研究途径，但这些p97在癌细胞中增加依赖性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修复和清除受损蛋白质的基本酶，特别是其在细胞对电离辐射的反应中的作用。这是一个基础科学研究方案，具有改善电离辐射治疗结果的巨大潜力。

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

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

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

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