Genetics and functional interactions in the mammalian DNA-damage response

DNA is continually being damaged by factors that arise from normal cell metabolism and from environmental agents. Our cells have evolved a large number of sophisticated proteins that detect this damage and, in most instances, mediate its effective repair. Defective repair of such damage occasionally occurs in normal cells and more often in cells with DNA-damage response (DDR) defects. This leads to mutations that disrupt cell function and can lead to cancer and other diseases.

Our proposed research builds on our past experience in identifying and characterising DDR proteins, and couples this with our recent successful implementation of novel CRISPR-Cas9 (a genome editing tool) and other technologies to systematically screen for new DDR proteins and regulators and characterise how they function.

Our research should provide new mechanistic insights into fundamental DDR processes. Furthermore, it will help explain how certain DNA-damaging chemotherapeutic agents and novel DDR enzyme targeted drugs kill cancer cells, and how cancers can evolve resistance to these therapeutic agents. This knowledge may also suggest ways to more effectively treat cancers, as well as various other genetic diseases that are caused by DDR defects.