CAREER: Role of the RFC Family Clamp Loader Ctf18-RFC in Sister Chromatid Cohesion

Indiana University, Bloomington IN

Investigators

Abstract

In dividing cells, newly replicated chromosomes are non-covalently linked during S-phase, a property called sister chromatid cohesion (SCC), until the onset of cell division. SCC is executed by a protein complex called Cohesin, and is essential for bi-allelic attachment of chromosomes to the mitotic spindle. In the absence of cohesin or the proteins required for its proper assembly on chromosomes (collectively referred to as cohesion establishment factors or CEFs), chromosome mis-segregation may occur, resulting in aneuploidy, a hallmark of many genetic disorders including cancer. Knowledge at the molecular level of how SCC is executed by CEFs will not only shed light on a vital cellular mechanism to avert chromosome mis-segregation, but may also reveal critical targets of genome surveillance pathways which function to prevent mitotic progression in the presence of defective chromosomes. Although current models propose that CEFs function to coordinate DNA replication with cohesion establishment, the mechanism by which the process is executed, and the precise role of each CEF is unclear. The focus of this project is on elucidating the role of the CEF Ctf18-RFC, which shares activities similar to the DNA replisome component RFC. A requirement for the RFC-like activities of Ctf18-RFC for SCC will be investigated by defining the domains of Ctf18-RFC required for its RFC-like function in vitro, and then correlating loss of its RFC-like function with impaired SCC in vivo. The very basic aspect of genetic inheritance addressed by this project is also the vehicle for our K-12 and undergraduate science education goals, which seek to broaden the base and depth of scientific knowledge acquired by students, and increase the number of students who choose careers in basic science research.