Grant: Operating Grant

We are studying the structure and function of the breast and ovarian cancer-linked protein, BRCA1, as well as a related protein called TopBP1. Our goal is to understand how these proteins function within cells to ensure that DNA damage is repaired. BRCA1 and TopBP1 form important parts of a complex network of proteins which recognize DNA damage and coordinate its repair. Our work has focused on one part of the BRCA1 protein, called the BRCT domain. Our previous work revealed the 3D structure of this part of the protein, and showed how the BRCT domain acts by making contacts to other proteins involved in responding to DNA damage. We were able to show that many of the mutations within BRCA1 which are associated with breast and ovarian cancers specifically disrupt this activity. We now know that BRCT domains are a common feature of many other important proteins which also control how cells respond to DNA damage. This study has three major themes. In the first, we will determine the structural and functional consequences for all the mutations within the BRCA1 BRCT domain that have been found in the human population through breast cancer screening programs. In the second theme, we will carry out experiments to understand how BRCA1 is ultimately brought to the sites of DNA damage through interactions involving chains of a protein called ubiquitin. In the third theme, we will probe the role of the TopBP1 protein, another member of the BRCT family of proteins which coordinates the response to problems in the replication of new DNA caused by DNA damage. The BRCT family of proteins is now known to be a critical class of proteins which control how cells respond to DNA damage. The study of these proteins will help us to understand why mutations in these proteins lead to an increased susceptibility to cancer, and could provide new routes for the targeted treatment of specific cancers.