IMPLICATIONS OF DNA REPLICATION FORK PROTEINS FOR CANCER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A unifying feature of cancer cells is an unstable genome. To achieve normal development, a cell must accurately coordinate pathways affecting DNA replication, chromosome segregation and DNA damage repair. Mishaps in any of these procedures can lead to instability in the genome and ultimately to a higher incidence of cancer development. Therefore, these mechanisms must be highly orchestrated and rigorously regulated. Accumulating evidence demonstrates that there are particular molecules that bridge these pathways to insure coordinate regulation. Many of these molecules have overlapping functions for DNA replication and repair and chromosome segregation. This study focuses on members of the RecQ helicase superfamily of proteins that function at replication forks and have roles in DNA repair and chromosome segregation. Bloom Syndrome is a recessive disorder resulting from mutation in the Bloom Syndrome gene (Blm) and characterized by increased genomic instability and enhanced onset of cancer. The physical and functional biochemical studies undertaken will identify and refine the sub-domains of Blm responsible for partnerships with known DNA repair and replication proteins to clarify the exact role of Blm in genomic stability. Furthermore, Chl1p is a newly identified RecQ family member in Drosophila and is implicated in bridging DNA replication and chromosomal cohesion. This study will identify the function of Chl1p in Drosophila by genetic deletion of the entire ORF for Chl1p. Overall, the experiments span the disciplines of biochemistry, molecular biology and genetics to investigate the RecQ protein partnerships responsible for the accurate progression through DNA replication, repair and chromosome segregation.