The Response to a Site-Specific Blocked DNA Replication Fork in Human Cancers

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DESCRIPTION (provided by applicant): The DNA damage response from exogenous double-strand breaks is well-studied, but the response to stalled replication forks that results in strand cleavage is less well understood. Homologous recombination (HR) has been predominantly studied as a mechanism of DNA double-strand break repair, but the major role of HR proteins in protecting the genome may be due to the homology-dependent repair of cleaved DNA replication forks. The recruitment of HR proteins to blocked or cleaved replication forks depends on BRCA1-BRCA2 pathway of HR, which we know is defective in a significant number of human cancers. The role of both proteins may not be the same in managing replication forks compared to double-strand breaks with two ends. By studying the consequences of a blocked DNA replication fork in detail, the goal is to develop new potential strategies for the therapy of BRCA-pathway deficient cancers. The first aim will determine events that occur as a result of replication fork block (RFB) and how the RFB is cleaved resulting in replication fork collapse. The second aim will determine what happens when there are defects in HR, resulting in genomic instability. Since HR-deficiency is a tumor-specific phenotype, the understanding of replication-associated events provides opportunities for novel therapeutics. For example, we need to understand how fatal chromosomal aberrations are created by replication-associated breaks in HR-deficient cells. The role of Replication Protein A, RAD52, and alternative end-joining are all potentially important in determining cell fate. The knowledge from these proposed experiments should allow new insight for treating human cancers with defects in this pathway.