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

该计划的实现不仅有助于获得有关DDR中p97及其适配器和底物的机械功能的知识，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。这些知识的影响和任何新的代理将有助于科学文献和影响正在进行的研究都在格雷研究所，在更广泛的大学研究界，以及国家和国际研究。鉴定参与电离辐射后DSB修复和/或DNA复制叉进展和稳定性的p97衔接子和底物的临床影响将提供强大的生物标志物工具。首先是建立癌症或基因组不稳定性诊断生物标志物;这方面的一个直接例子是我们在遗传上未表征的WRN样综合征中发现了C1 orf 124/DVC 1突变。这项工作对精确癌症预后的生物标志物以及治疗干预的预测生物标志物也具有重要意义。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。

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.