Identification of Proteins Required for Repair of Double-Strand Chromosome Breaks, a Predisposing Factor in Breast Cancer

摘要

Defects in repair of double strand chromosome breaks (DSBs) are emerging as important factors both in familial and sporadic breast tumors. Just as a bacterial model for single-base mismatch repair lead to rapid identification of human homologues with roles in carcinogeneis, development of a bacterial model for DNA DSB repair will provide important insights into the role this system plays in breast tumor development. This project has focused on developing a bacterial model for DSB repair by characterizing the enzymatic apparatus needed to initiate DNA replication on recombination intermediates. We describe how the initiation of PriA helicase activity on the DNA fork is influenced by both fork structure and by single-strand DNA binding protein. The two factors may direct PriA helicase to translocate along the lagging-strand template of forked DNA to facilitate PriA's 3' to 5' helicase activity to unwind the DNA duplex and promote loading of the replicative helicase DnaB, a central step in assembly of the replisome. These data indicate that PriA is an initiator protein that responds to DNA damage and assembles the components necessary for repair by replication, maintaining the integrity of the chromosome and preventing potentially catastrophic loss of information and mutation.