Molecular insights into ubiquitin remodelling factor p97(VCP) in DNA damage response and genome stability

泛素重塑因子 p97 (VCP) 在 DNA 损伤反应和基因组稳定性中的分子洞察

• 批准号: MC_EX_MR/K022830/1
• 负责人: Kristijan Ramadan
• 金额: $ 204.63万
• 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: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_EX_MR%2FK022830%2F1
• 关键词: Molecular; insights; into; ubiquitin; remodelling

Your body is built of billions of cells, and they all have to work as a team. Almost everything a cell does involves a protein. Proteins relay decisions, build structures, translate genetic instructions, repair damage, and carry signals. So it is not surprising that cancer is marked by proteins not working properly. Sometimes the proteins fail; sometimes they do their job too well, or do it at the wrong time.Proteins are created and recycled constantly; this makes sure that proteins do not get old and damaged. The balance between making and recycling proteins is kept in tight check, making sure that the amount of a given protein is just right. Our work focuses on the way cells recycle proteins. We know that proteins that are old or not needed are labelled for recycling with a tag called ubiquitin. Huge recycling machines called proteasomes grab hold of the ubiquitin handle and recycle the attached protein. We don't know in detail when and how the ubiquitin label is attached. We want to know how this works during the process of repairing damaged DNA. Damaged DNA can be a starting point for cancer; but it's also the key to effective radio- and chemotherapy. If we knew how cells recycle the proteins that repair radiation and chemotherapeutic damage to DNA then we would be able to design ways to make radio- and chemotherapy more effective.This grant will fund research to improve our understanding of the proteins involved in DNA damage repair and the processes that recycle them.

你的身体是由数十亿个细胞组成的，它们都必须作为一个团队工作。细胞所做的一切几乎都与蛋白质有关。蛋白质传递决定，构建结构，翻译遗传指令，修复损伤，并携带信号。因此，癌症的标志是蛋白质不能正常工作，这并不奇怪。有时蛋白质会失效;有时它们做得太好了，或者做得不对。2蛋白质不断地被创造和回收; 3这确保了蛋白质不会变老和损坏。制造和回收蛋白质之间的平衡受到严格控制，确保给定蛋白质的量恰到好处。我们的工作重点是细胞回收蛋白质的方式。我们知道，旧的或不需要的蛋白质被称为泛素的标签标记为回收。被称为蛋白酶体的巨大回收机器抓住泛素手柄并回收附着的蛋白质。我们不知道泛素标签是何时以及如何附着的细节。我们想知道在修复受损DNA的过程中这是如何工作的。受损的DNA可能是癌症的起点;但它也是有效的放射和化疗的关键。如果我们知道细胞如何回收修复DNA辐射和化疗损伤的蛋白质，那么我们将能够设计使放射和化疗更有效的方法。这笔赠款将资助研究，以提高我们对DNA损伤修复所涉及的蛋白质及其回收过程的理解。

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

SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells.

• DOI: 10.1038/s41419-021-03437-w
• 发表时间: 2021-02-08
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Na J;Newman JA;Then CK;Syed J;Vendrell I;Torrecilla I;Ellermann S;Ramadan K;Fischer R;Kiltie AE
• 通讯作者: Kiltie AE

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

The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair.

• DOI: 10.1016/j.molcel.2018.02.002
• 发表时间: 2018-03-01
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Baranes-Bachar K;Levy-Barda A;Oehler J;Reid DA;Soria-Bretones I;Voss TC;Chung D;Park Y;Liu C;Yoon JB;Li W;Dellaire G;Misteli T;Huertas P;Rothenberg E;Ramadan K;Ziv Y;Shiloh Y
• 通讯作者: Shiloh Y

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