Department of Biochemistry & Biophysics
Ph.D., Molecular and Cell Biology
Curriculum Vitae [.pdf]
- Regulation of DNA replication in mammalian cells
We are interested in understanding the regulation of DNA replication in mammalian cells, a process that is tightly controlled in normal cells, but deregulated in cancer. Replication is largely controlled through the assembly of a “pre-replication complex” at chromosomal origins consisting of ORC, the MCM complex, Cdt1, and Cdc6. We propose that DNA replication control is integrated with the array of cellular signaling events that coordinate cell cycle progression and cell fate determination. We further suggest that the interface between replication control and these signaling pathways involves protein-protein interactions between components of the pre-replication complex and other cellular systems. Our goal is to identify those points of interface and to further explore the importance of protein interactions in replication control.
Our current investigations are focused on the following questions:
1) What are the specific functional domains in Cdc6 and Cdt1 that are responsible for interaction with pre-replication complex components, and what are the cellular consequences that arise from manipulation of those interactions?
2) What role does phosphorylation play in controlling the abundance and activity of Cdc6 and Cdt1? Does phosphorylation regulate critical protein-protein interactions within the complex?
3) What cellular proteins associate with Cdc6 and Cdt1; do newly-identified partners represent novel regulators of Cdc6/Cdt1? Molecular genetic screens have been performed to identify candidate proteins that interact with Cdc6 or Cdt1. These factors include a protein phosphatase, a ubiquitin ligase, and components of the chromosome segregation machinery.
Click above for PubMed publications.
- Cook, J.G., Chasse, D.A.D. , and Nevins, J.R. (2004) The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells. The J Biol Chem 279(10): 9625-33. Abstract
- Cook, J.G., Park, C.H., Burke, T.W., Leone, G., DeGregori, J., Engel, A., and Nevins, J.R. (2002) Analysis of Cdc6 function in the assembly of mammalian prereplication complexes. Proc Natl Acad Sci USA 99(3): 1347-52. Abstract
- Burke, T. W., Cook, J.G., Asano, M., and Nevins, J.R. (2001) Replication Factors Mcm2 and Orc1 Interact with the Histone Acetyltransferase HBO1. The J Biol Chem 276(18): 15397-408. Abstract