Implications of DNA Replication Fork Proteins for Cancer (2009 - Present)

Investigator:  Karen Almeida, Rhode Island College
Mentor:  Susan Gerbi, Brown University 

Abstract:  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 grant application focuses on members of the RecQ helicase superfamily of proteins that function at replication forks and have roles in DNA repair and chromosome segregation.

Defects or mutations in many RecQ family member genes manifest in human disease states. 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 a wide array of cancer types. Blm plays a role in the stabilization of stalled replication forks, often due to persistent DNA damage during S phase. The protein biochemical studies proposed herein will identify and refine the sub-domains of Blm responsible for partnerships with known DNA repair and replication proteins such as Fen1, BRCA1 and Nbs1.