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Last Updated: 5/16/2007
| Jean G Cook, Ph.D.
Assistant Professor |  |
Research Interests
Integrating DNA replication control with checkpoint signaling.
Our lab studies DNA replication licensing, which is the process that renders individual chromosomal segments competent to be duplicated. Licensing involves the construction of a multiprotein complex at replication origins called the pre-replication complex, or "preRC." PreRC assembly is only permitted during the G1 period of the cell cycle, and only in cellular environments that are compatible with cell division. For example, if the DNA is damaged, specific preRC proteins are inhibited or degraded so that cells don't duplicate their chromosomes inappropriately. Cells employ a variety of "checkpoint" signaling pathways to coordinate progression through the cell division cycle with a wide variety of extracellular and intracellular information. We seek to understand how the preRC assembly process is linked to these signaling pathways. It's clear that cancer cells have mutations that disrupt cell cycle checkpoints, but we still don't fully understand how those checkpoints are supposed to operate in normal cells. Our primary focus is on the regulation and function of two critical preRC proteins, Cdc6 and Cdt1. Some of the questions currently under study are:
How is the replication licensing factor Cdc6 recognized by the checkpoint pathway for degradation after DNA damage?
What happens to Cdc6 and/or Cdt1 when cell experience other forms of stress?
How do cells behave when replication licensing is blocked?
How do cells behave when replication licensing is hyperactive?
We manipulate various replication and checkpoint proteins in human cell lines using a variety of molecular genetic tools. We deplete proteins from cells using siRNA techniques, overproduce proteins using recombinant plasmid or viral vectors, and inhibit activities with pharmacological reagents. Ultimately we hope to achieve a greater understanding of normal cell cycle control, so that future tools for cancer diagnosis and therapy can be developed.
For more detailed information, as well as an introduction to the members of the Cook lab, visit our webpage http://www.med.unc.edu/~jgcook/
Recent Accomplishments and Honors
Recipient of the Howard Temin Award from the National Cancer Institute
Training
Ph.D., University of California, Berkeley
Postdoctoral work at Duke University Medical Center with Dr. Joseph R. Nevins
Publications
Braden WA, Lenihan JM, Lan Z, Luce KS, Zagorski W, Bosco E, Reed MF, Cook JG, Knudsen ES. (2006)Distinct action of the retinoblastoma pathway on the DNA replication machinery defines specific roles for cyclin-dependent kinase complexes in prereplication complex assembly and S-phase progression.
Mol Cell Biol. 2006 Oct;26(20):7667-81
Cook, J.G., D.A.D. Chasse, and J.R. Nevins (2004) The Regulated Association of Cdt1 with Minichromosome Maintenance Proteins and Cdc6 in Mammalian Cells. The Journal of Biological Chemistry 279: 9625-9633.
Cook, J.G., C.-H. Park, T.W. Burke, G. Leone, J. DeGregori, A. Engel, and J.R. Nevins (2002) Analysis of Cdc6 function in the assembly of mammalian pre-replication complexes. Proceedings of the National Academy of Sciences U.S.A. 99: 1347-1352.
Burke, T. W., J.G. Cook, M. Asano, and J.R. Nevins (2001) Replication Factors Mcm2 and Orc1 Interact with the Histone Acetyltransferase Hbo1. The Journal of Biological Chemistry 276: 15397-15408.
Leone, G., J. DeGregori, L. Jakoi, J.G. Cook, and J.R. Nevins (1999) Collaborative role of E2F transcriptional activity and G1 Cdk activity in the induction of S phase. Proceedings of the National Academy of Sciences U.S.A. 96: 6626-6631.
E-mail: jean_cook@med.unc.edu
Telephone: 919-843-3867
Address: 508 Mary Ellen Jones Building Chapel Hill, NC 27599
URL: http://www.med.unc.edu/~jgcook/
