Tumor Suppression by BRCA1: A Critical Role at DNA Replication Forks

PUBLIC ABSTRACT

The DNA molecule carries all the genetic information necessary for a cell to grow and develop normally. This information has to faithfully replicate before cell division, in order to be transmitted to the daughter cells. Several molecular mechanisms exist to prevent mistakes during the transmission of this genetic information. The BRCA1 protein is a tumor suppressor gene the mutant of which predispose to breast and ovarian cancers. Mutations in the BRCA1 gene occur in about 40% of familial breast cancer. BRCA1 plays an important role in DNA homologous recombination repair and is important in maintaining genome integrity. At the present time, it is not clear how does BRCA1 exerts its tumor suppressor role. Therefore, we suggest studying the role of BRCA1 at the site of DNA duplication, called replication fork. We hypothesize that BRCA1 may facilitate the DNA repair process on stalled replication fork. We would like to address the question whether BRCA1 constitutively bound to the fork or it is recruited following DNA damage. We will use a vertebrate cell-free system derived from Xenopus eggs to investigate BRCA1 role in tumorigenesis. This system will enable us for the first time to investigate replication in the complete absence of BRCA1. By probing the possible role of BRCA1 at the replication fork, a novel concept bringing together previous observations, we anticipate uncovering new rational bases for innovative therapeutics to treat breast cancer.