Associate Professor of Biochemistry & Biophysics, UNC-CH
PHD - University of California, Berkeley(click for Full Publication List)
HONORS & AWARDS
- Academy of Educators Elected Fellow, 2012
- The Jefferson-Pilot Fellowship in Academic Medicine, 2010-2014
- Academy of Educators Teaching Excellence Award, 2010
- National Cancer Institute's Howard Temin Award, 2003-2008
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." In order to duplicate vast eukaryotic genomes, preRCs must be assembled at thousands of individual origins, but each of those origins must only be permitted to initiate replication once per cell cycle. PreRC assembly is under very tight regulation to prevent re-replication, which could lead to genome instability, cell death, or cancer. PreRC assembly is only permitted during the G1 period of the cell cycle (A), 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 (B). 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.
- human cell culture
- protein-protein interactions
- recombinant DNA technology
- Varma, D., S. Chandrasekaran, L.J.R. Sundin, K.T. Reidy, D.A.D. Chasse, K.R. Nevis, J.G. DelUca, E.D. Salmon, and J.G. Cook (2012) Recruitment of the human Cdt1 replication licensing protein by the loop domain of Hec1 is required for stable kinetochore microtubule attachment, in press Nature Cell Biology
- Chandrasekaran, S., T.X. Tan, J.R. Hall, and J.G. Cook (2011) Stress-activated MAP kinases, p38 and JNK, control the stability and activity of the Cdt1 DNA replication licensing factor. Molecular and Cellular Biology 31(22):4405-4416.
- Taylor, S.M., K.R. Nevis, H.L. Park, G.C. Rogers, S.L. Rogers, J.G. Cook, and V.L. Bautch (2010) Angiogenic factor signaling regulates centrosome duplication in endothelial cells of developing blood vessels Blood 116(16): 3108-3117 PMCID :PMC2974614
- Nevis, K.R., M. Cordeiro-Stone, and J.G. Cook (2009); Origin licensing and p53 status regulate Cdk2 activity during G1. Cell Cycle,8(12)1952-1963. PMCID: PMC2972510 (Profiled by Ge, X.Q. and J.J. Blow (2009) “The licensing checkpoint opens up.” Cell Cycle 8:2320-22.)
- Sotillo, E., J. Garriga1, A. Padgaonkar; A. Kurimchak; J. G. Cook, and X. Graña (2009),*Coordinated Activation of the Origin Licensing Factor Cdc6 and Cdk2 in Resting Human Fibroblasts Expressing SV40 Small t Antigen and Cyclin E. The Journal of Biological Chemistry, 284(22):14126-35 PMCID: PMC2682861
- Liu, P., D.M. Slater, M. Lenburg, K. Nevis, J.G. Cook, and C. Vaziri (2009); Replication licensing promotes Cyclin D1 expression and G1 progression in untransformed human cells. Cell Cycle, 8(1):125-136. PMCID: PMC3032797.
- J.G.Cook; Replication licensing and the DNA damage checkpoint (2009). Frontiers in Bioscience, invited review, 14:5013-5030. PMCID: PMC3032801
120 Mason Farm Rd
Campus Box # 7260
3062 Genetic Medicine Bldg
Chapel Hill, NC 27599
Lab Location: 3070G-H Genetic Medicine