Post-Translational Modifications in the Radiation Damage Response

辐射损伤反应的翻译后修饰

• 批准号: MC_UU_00001/1
• 负责人: Kristijan Ramadan
• 金额: $ 319.57万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00001%2F1
• 关键词: Post; Translational; Modifications; Radiation; Damage

DNA replication and DNA repair are two essential processes for genome amplification and stability. Defects in these two processes lead to genome instability and various human diseases such as premature aging and cancer. We have recently identified that the ubiquitin dependent AAA ATPase p97 plays an essential role in the regulation of DNA replication and DNA repair. The specificity of p97 in the regulation of DNA replication and DNA repair is governed by p97 cofactors. Now, we aim to identify and characterise the p97 system (p97/VCP + cofactors) involved in the regulation of DNA replication and DNA repair. Our current results demonstrate that mutations in p97 cofactors lead to cancer and premature aging in humans. Further identification and characterisation of the p97 system will help us to understand why mutations in p97 cofactors lead to cancer. We will use biochemical and cell biological approaches to delineate molecular mechanisms of the p97 system in DNA replication and repair. Given that cancer cells divide much faster than the majority of human cells and have altered metabolism, which leads to elevated DNA damage, the p97 system has emerged as an attractive drug target for cancer therapy. This award aims to demonstrate a new concept, which is based on the hypothesis that the survival and chemoresistance of many cancers depends on the p97 system, and will pave the way for identification of potential p97 system inhibitors for cancer therapy.

DNA复制和DNA修复是基因组扩增和稳定的两个基本过程。这两个过程中的缺陷导致基因组不稳定和各种人类疾病，如过早衰老和癌症。我们最近发现，泛素依赖的AAA ATP酶p97在DNA复制和DNA修复的调节中起着至关重要的作用。p97在DNA复制和DNA修复调节中的特异性由p97辅因子控制。现在，我们的目标是确定和鉴定p97系统（p97/VCP +辅因子）参与调节DNA复制和DNA修复。我们目前的研究结果表明，p97辅因子的突变会导致人类癌症和过早衰老。对p97系统的进一步鉴定和表征将有助于我们理解为什么p97辅因子的突变会导致癌症。我们将使用生物化学和细胞生物学方法来描述p97系统在DNA复制和修复中的分子机制。鉴于癌细胞分裂速度比大多数人类细胞快得多，并且代谢改变，导致DNA损伤增加，p97系统已成为癌症治疗的有吸引力的药物靶点。该奖项旨在展示一个新的概念，该概念基于许多癌症的生存和耐药性取决于p97系统的假设，并将为识别潜在的p97系统抑制剂用于癌症治疗铺平道路。

项目成果

Interplay between base excision repair protein XRCC1 and ALDH2 predicts overall survival in lung and liver cancer patients.

• DOI: 10.1007/s13402-018-0390-8
• 发表时间: 2018-10
• 期刊: Cellular oncology (Dordrecht, Netherlands)
• 作者: Chen X;Legrand AJ;Cunniffe S;Hume S;Poletto M;Vaz B;Ramadan K;Yao D;Dianov GL
• 通讯作者: Dianov GL

Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review.

• DOI: 10.1042/bst20200861
• 发表时间: 2021-06-30
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Bolland H;Ma TS;Ramlee S;Ramadan K;Hammond EM
• 通讯作者: Hammond EM

A three-in-one-bullet for oesophageal cancer: replication fork collapse, spindle attachment failure and enhanced radiosensitivity generated by a ruthenium(ii) metallo-intercalator.

• DOI: 10.1039/c7sc03712k
• 发表时间: 2018-01-28
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Gill MR;Jarman PJ;Halder S;Walker MG;Saeed HK;Thomas JA;Smythe C;Ramadan K;Vallis KA
• 通讯作者: Vallis KA

DNA protein crosslink proteolysis repair: From yeast to premature ageing and cancer in humans.

• DOI: 10.1016/j.dnarep.2018.08.025
• 发表时间: 2018-11
• 期刊: DNA repair
• 影响因子: 3.8
• 作者: Fielden J;Ruggiano A;Popović M;Ramadan K
• 通讯作者: Ramadan K

A unified model for the G1/S cell cycle transition.

• DOI: 10.1093/nar/gkaa1002
• 发表时间: 2020-12-16
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Hume S;Dianov GL;Ramadan K
• 通讯作者: Ramadan K