DNA replication forks and checkpoints

Our genomes are under constant attack: extraterrestrial radiation as well as intracellular water and oxygen continually damage our DNA in a variety of ways. When the DNA replication machinery encounters damaged DNA, it stops and activates a DNA ‘checkpoint’ pathway which regulates a variety of cellular activities, but, most importantly, it maintains the function of the stalled replication machinery. 

We will use biochemistry with purified proteins along with genetics and cell biology in yeast and human cells to understand how different forms of DNA damage activate the checkpoint and how the checkpoint protects stalled replication. 

Cancer cells have high levels of genome instability, which provides the fuel for tumour evolution. Many chemotherapeutic drugs work by damaging DNA and interfering with DNA replication. Our work could contribute to understanding drivers of genome instability in cancer, designing better chemotherapies and understanding how resistance to chemotherapies emerges.