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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

基本信息

批准号：
MC_PC_12001/1
负责人：
Kristijan Ramadan
金额：
$ 27.78万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Intramural
财政年份：
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_PC_12001%2F1
关键词：
Molecular insights into ubiquitin remodelling

项目摘要

The realisation of this programme will not only contribute to gaining knowledge about the mechanistic function of p97, its adapter and substrates, in the DDR, but will also have a direct impact on the development of novel small-molecule molecularly-targeted cancer drugs for use in combination therapy. The impact of this knowledge and any new agents will contribute to the scientific literature and influence on-going research both within the Gray Institute, the research community in the wider University, and national and international research. The clinical impact of identifying p97 adapters and substrates that are involved in DSB repair after ionizing-radiation and/or DNA replication fork progression and stability will be to provide powerful biomarker tools. First the establishment of cancer or genome instability diagnostic biomarkers; a direct example of this is our discovery of C1orf124/DVC1 mutation in genetically uncharacterized WRN-like syndrome. This work also has ramifications of importance for biomarkers for precise cancer prognosis, as well as predictive biomarkers for therapeutic intervention. Thus clinicians will have a range of powerful tools that are able to identify patient groups, understand their cancer progression and predict their treatment outcome.

该计划的实现不仅有助于获得p97及其适配器和底物在DDR中的机制功能的知识，而且还将对用于联合治疗的新型小分子分子靶向癌症药物的开发产生直接影响。这些知识和任何新媒介的影响都将有助于科学文献，并影响格雷研究所、更广泛的大学研究界以及国内和国际研究中正在进行的研究。鉴定参与DSB电离辐射修复和/或DNA复制叉进展和稳定性的p97适配器和底物的临床影响将提供强大的生物标志物工具。首先建立癌症或基因组不稳定性诊断生物标志物；一个直接的例子是我们在基因未表征的wrn样综合征中发现了C1orf124/DVC1突变。这项工作还对精确癌症预后的生物标志物以及治疗干预的预测性生物标志物具有重要意义。因此，临床医生将拥有一系列强大的工具，能够识别患者群体，了解他们的癌症进展并预测他们的治疗结果。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

Targeting TOPK sensitises tumour cells to radiation-induced damage by enhancing replication stress.

DOI：
10.1038/s41418-020-00655-1
发表时间：
2021-04
期刊：
Cell death and differentiation
影响因子：
12.4
作者：
Herbert KJ;Puliyadi R;Prevo R;Rodriguez-Berriguete G;Ryan A;Ramadan K;Higgins GS
通讯作者：
Higgins GS

Immunofluorescence microscopy-based detection of ssDNA foci by BrdU in mammalian cells.