DNA damage is a major cause of genetic instability, which can give rise to cancer. To prevent genomic alterations caused by DNA damage, cells invoke various mechanisms to inhibit DNA replication while allowing DNA repair. Previous studies have suggested that proliferating cell nuclear antigen (PCNA) is an important regulator in modulating this differential regulation process. This proposal is designed to study the role of DNA- dependent kinase (DNA-PK) in regulating another key replication factor-RPA's activity in response to DNA damage. DNA-PK is a nuclear protein involved in double-strand breaks (DSBs) damage repair and genetic recombination. Based on our preliminary data, we hypothesize that RPA is the key target for DNA-PK, and that DNA-PK may modulate RPA activity via a damage-inducible inhibitory factor, which may interfere with RPA's function in replication, but not in nucleotide excision repair. We believe that our proposal is based on the solid preliminary data that were recently carried out in our laboratory. Even though the long term goal of our research group is to understand the damage checkpoint control and intra-S phase arrest, this study will surely provide some valuable information about the mechanism by which cells respond to DNA damage, and hopefully will also influence other areas of cancer research.
