Genomic Instability and DNA Repair Laboratory

The genome of our cells is under constant attack by DNA damaging agents from both endogenous and exogenous sources. Cells have evolved a complex system, termed the DNA damage response (DDR) that detects DNA damage, signals its presence to the cell and sets about repairing this damage. The DDR is crucial for cell survival and to guard against cancer. Failure of these DDR pathways can destabilize the genome and have devastating consequences for human development and health. Importantly, DDR proteins play key roles in preventing cancer, and their activities, in part, determine the outcome of cancer radiotherapy and chemotherapy. To restore genomic integrity, damaged DNA needs to be repaired, which require accumulation of repair proteins to the sites of damage. We and others have discovered that polycomb group (PcG) proteins are recruited to the sites of DNA double-strand breaks (DSBs) and are required for efficient DSB repair (Ismail et al JCB, 2010). Furthermore, we have demonstrated that PcG-mediated ubiquitylation event creates a ‘mark’ on the chromatin around the site of DNA damage that mediates recruitment of several DDR proteins. In my lab we are trying to understand how cells respond when their DNA is damaged, in particular how proteins signal and repair DSBs. Our aims are to: identify new DDR proteins (using high throughput siRNA library screens) ; determine how these proteins function; see how DDR events are affected by chromatin structure; and understand how the DDR impacts diverse cellular events. Towards this end, we are using a broad range of Biochemical, Biophysical and Cell biology techniques and approaches in mammalian cells. Our ambition is to understand how defects in the DDR can lead to diseases such as cancer; neurodegenerative diseases and premature aging, and how such diseases might be better diagnosed and treated.