Catherine A. Fox

We are interested in the structure and function of eukaryotic chromosomes and focus primarily on understanding how chromosome structure, at the levels chromatin and nuclear architecture, regulate DNA replication and gene expression. We combine classical and reverse genetics, molecular and structural biology, biochemistry and whole genome methods in the budding yeast Saccharomyces cerevisiae. Projects include:

1. Mechanisms that regulate target-site selection and function of the Origin Recognition Complex (ORC)
ORC is a complex of 6 different proteins conserved from yeast to humans. Its main job is to function in DNA replication at sites called origins, the positions where DNA replication initiates. Eukaryotic chromosomes have an excess of replication origins, and at some origins ORC has additional functions in chromatin structure. These two different roles of ORC may be regulated by how ORC binds to DNA and chromatin. ORC-chromatin interactions play a larger role than ORC-DNA interactions in ORC binding in human compared to yeast cells. But we have discovered a subset of poorly studied yeast origins that also rely heavily on ORC-chromatin interactions. Biochemical, whole-genome, and classic genetics are being used to study these novel origins.

2. Structure-function studies of protein-protein interactions involving ORC
ORC interacts with many different proteins that regulate its function. We study ORC’s interaction with protein-partners that endow it with unique functions in chromatin structure. We have used structural biology, in collaboration with our colleague Dr. Jim Keck, to study protein-protein interactions involving ORC. We are also studying domains in ORC that control ORC-chromatin interactions in collaboration with our colleague Dr. John Denu using both molecular and chemical biology approaches.

3. Cell-cycle regulation of chromosome structure and chromosome-associated proteins
Chromosome structure is dynamic during every cell cycle. Proteins that regulate the association of chromosomes with the nuclear membrane help control cell cycle regulated changes in chromatin structure. We are using unbiased forward genetic screens to reveal novel genes that modulate chromosomal architecture within the nucleus and in response to cell cycle changes. A variety of approaches are being used to study these genes and their encoded proteins.