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

这一计划的实现不仅将有助于了解p97及其接头和底物在DDR中的机制功能，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。这一知识和任何新的推动者的影响将有助于在格雷研究所、更广泛的大学的研究界以及国内和国际研究中促进科学文献和正在进行的研究。在电离辐射和/或DNA复制分叉进展和稳定后，识别参与DSB修复的p97接头和底物的临床影响将是提供强大的生物标记工具。首先，建立癌症或基因组不稳定的诊断生物标记物；一个直接的例子是我们在遗传上没有特征的WRN样综合征中发现了C1orf124/DVC1突变。这项工作对准确预测癌症预后的生物标记物以及治疗干预的预测性生物标记物也具有重要意义。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.