Targeting the function of BRCA1 in the DNA damage response network.

Breast cancer type 1 susceptibility (BRCA1) protein is a protein encoded by the tumour suppressor gene of the same name, BRCA1. Although involved in several cellular processes such as apoptosis, activation of cell-cycle check points, ubiquitination and transcription regulation, this project will primarily focus on the role of BRCA1 in DNA damage response (DDR). The BRCA1 protein possesses a tandem repeat of the functional domain, BRCA1 C-terminus domain (BRCT). The BRCT domains of BRCA1 are of particular interest as the structural arrangement of the protein forms a cleft, enabling a binding pocket for phosphorylated serine on the N-terminal repeat and a hydrophobic pocket for binding phenylalanine on the C-terminal repeat. Capacity to bind with phosphorylated protein partners containing a pSPxF motif is necessary for BRCA1 to fulfil its role in DNA repair and tumour suppression. To investigate the mechanisms of these protein-protein interactions and probe the function of BRCA1 in the cellular environment, this project will utilise a collection of Affimer proteins as binding partners for wild type and mutant forms of BRCA1. The development of a workflow that can elucidate the DDR mechanisms of BRCA1 could be applied to other proteins with BRCT domains in order to understand the broader biological significance of these domains in DDR, tumour suppression and cancer biology overall.