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

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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.