Our team studies the mechanisms that help preserve the stability of the human genome, and probes how these systems go awry in diseases like cancer.
All cells must replicate their DNA prior to cell division, via a complex process during which the genome is particularly vulnerable. Any event that disrupts - or stalls - the process of DNA replication is referred to as ‘replication stress’ (RS). RS foreshadows genome instability in a number of human diseases, and is a crucial factor in the initiation and progression of many sporadic and inherited cancers. RS can be caused by oncogene activation and certain chemotherapies, as well as cellular metabolites such as aldehydes, which are also present in cigarette smoke, and which are elevated following alcohol consumption. Replication impediments can lead to fork collapse and generation of DNA breaks, and to avoid this scenario the cell orchestrates the recruitment of factors that act collectively to stabilise and restart the stalled replication fork. Co-ordination of DNA replication and break repair is therefore a crucial aspect of genome maintenance.
We are studying how a series of previously uncharacterised proteins are recruited to DNA breaks and stalled replication forks, and how they function at these sites to protect the cell from DNA damage, and thus mediate resistance to chemo and radiotherapy.