The DNA Damage Response (DDR) is a major component of a cells defence against disease. It serves to recognize and repair DNA damage, regulate gene expression, control cell-cycle progression and where necessary, to promote programmed cell death. One of the most potentially dangerous forms of DNA damage is a double stranded DNA break (DSB), which must be dealt with quickly to preseve the structural and genetic integrity of a cell. Failure to do so results in the generation of genomic aberrations such as chromosomal translocations that are potentially tumorigenic.
A key protein required for the repair of DNA breaks is the breast cancer-associated tumour suppressor, BRCA1. Defects in BRCA1 lead to a massive increase in genomic instability and formation of tumours. We are studying how BRCA1 functions to repair DNA breaks and how it suppresses other repair pathways to increase the accuracy of this repair. We recently showed that BRCA1 is able to influence the availability of DNA in a cell by regulating its folding into chromatin, enabling it to control important cellular functions such as DNA repair, transcription and replication. Moreover we have found that this is achieved through the BRCA1-dependent modification of histone protein with a polypeptide called ubiquitin.
This project will investigate how ubiquitylation of chromatin by BRCA1 affects cellular functions and identify the downstream regulatory components in this process using biochemical and cell biological approaches, high throughput screening and high-resolution immunofluorescence microscopy. Our goal is to identify new targets for therapeutic intervention in cancer.