Function of BRCA1 at a DNA Replication Origin

摘要

Hereditary predisposition to breast cancer is associate with mutations in the BRCA1 gene. BRCA1 functions as a tumor suppressor that is activated in response to DNA damage and the loss of normal BRCA1 activity leads to an increase in chromosome instability. BRCA1 is thought to respond to DNA damage incurred during S phase, but it is not clear precisely how BRCA1 recognizes DNA damage or transmits effector signals to delay cell cycle progression and allow efficient repair of damaged DNA. In this proposal, we present preliminary data that BRCA1 functions in a DNA checkpoint response for the origin of Epstein-Barr Virus DNA replication (Ori P). OriP replicates once and only once per cell cycle in synchrony with the cellular genome, and is therefore considered a valid model system for cellular replication origins. Importantly,, chromosomal replication proteins, including the origin recognition complex (ORC) and the licensing helicase complex (MCMs) associate with OriP. We have recently found that BRCA1 can be recruited to OriP in response to DNA damaging agents. We propose to study the mechanism of BRCA1 recruitment to OriP, its dependence on DNA- damage induced post-translational modifications, and to investigate its function at OriP in DNA replication and plasmid maintenance. We propose that these studies will provide valuable information concerning the function of OriP at replication origins and in the control of DNA replication initiation and genome stability.