UNMC College of Dentistry - Departments & Centers

Dr. Gregory G. Oakley

Title: Assistant Professor

Address
Room: 42
UNMC College of Dentistry
40th and Holdrege
Box 830740
Lincoln, NE 68583-0740

Oral Biology Department

Telephone: (402) 472-3519
Fax: (402) 472-2551
email: goakley@unmc.edu

Education:

Bachelor of Pharmacy, University of Kentucky, Lexington, KY
B.S. (Biology), University of Kentucky, Lexington, KY
Ph.D. (Toxicology), University of Kentucky, Lexington, KY

Research Interests:

Our research interests lie in the area of DNA damage and repair. Specifically, our research focuses on the signal transduction pathways that regulate the cellular responses to DNA damage and how alterations in these pathways contribute to mutagenesis and, ultimately, carcinogenesis. Current studies involve the biochemical activities of the protein complex, M/R/N (composed of Mre11, Rad50 and NBS1), and RPA, and how they work cooperatively and function in the replication stress response. Our primary goal is to achieve an understanding of the mechanistic roles of these proteins and how they cooperate to maintain genomic integrity.
To this end we are investigating the interaction between these proteins and determining the role phosphorylation plays in this protein-protein interaction. By identifying the exact protein-protein interaction will reveal possible sites and peptides involved in phosphorylation and begin to address the involvement phosphorylation plays in this interaction. The identification of the phosphorylated residues that coordinate interaction between RPA and the MRN complex and the kinase(s) responsible for phosphorylation of these proteins will be important in understanding how the MRN complex and RPA promote and signal damage recognition and repair of stalled and collapsed replication forks. Further work will involve the identification of other proteins involved in these processes including MDC1, FANCD2 and ATR and their involvement in the recruitment and function of the MRN complex and RPA at sites of DNA damage.
From a translational aspect other projects focus on approaches that exploit differential expression patterns between normal and cancer cells to improve the selectivity of treatment with anticancer agents. For example, lack of phosphorylation of Mre11 or RPA in cancer cells due to loss of kinase activity in cancer cells may make them selectively more susceptible to chemotherapeutic agents that target DNA replication or repair. These observations have important clinical implications. First, by analyzing the integrity of the MRN-RPA pathway in fresh human tumors (e.g., by examining RPA phosphorylation or Mre11 phosphorylation), one may predict the relative chemotherapeutic sensitivity of the tumors. Serial analysis of MRN/RPA in matched tumor samples from the same cancer patient may allow one to detect the serial onset of chemotherapeutic resistance. Second, we predict that small molecule inhibitors of RPA or Mre11 phosphorylation may block replication fork repair, thus, resensitizing tumors to the cytolytic effect of chemotherapeutic agents. Such small molecule inhibitors may serve as an important adjunct to conventional cancer chemotherapy

Grants:

Nebraska Center for Cellular Signaling, 12/05-06/08 NIH, $9,043,604; Principal Investigator: M.J. Wheelock; Project Leader: G. Oakley
American Cancer Society Ohio Division Pilot Research 09/04-08/06Principal Investigator: G. Oakley

Recent Publications:

G. G. Oakley, L. I. Loberg, J. Yao, M. Zernik-Kobak, M. P. Carty, K. K. Khanna, M. F. Lavin and K. Dixon. (2001) UV-induced Hyperphosphorylation of Replication Protein A Depends on DNA Replication and Expression of ATM Protein. Molecular Biology of the Cell, 12: 1199-1213
G. G. Oakley, A. L. Roe, R. A. Blouin, T. C. Ganguly, M. Vore, T.P. Twaroski, H.J. Lehmler and L.W. Robertson. (2001) Activation of AP-1 and STAT transcription factors by non-coplanar polychlorinated biphenyls (PCBs). Molecular Carcinogenesis 30: 199-208
N.M. King, G. G. Oakley, M. Medvedovic, and K. Dixon. (2001) The XPA protein alters the specificity of ultraviolet light-induced mutagenesis in vitro. Environmental and Molecular Mutagenesis 37: 329-339
D.W. Nebert, A.L. Roe, S.L. Vandale, E. Bingham and G.G. Oakley. (2002) NAD(P)H:quinine oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: a HuGE review. Genetics in Medicine 4: 62-70
G. G. Oakley, S. M. Patrick, J. Yao, M.P. Carty, J. J. Turchi and K Dixon. (2003) RPA Phosphorylation at Mitosis Alters DNA Binding and Protein/Protein Interactions. Biochemistry 42: 3255-3264
H. G. Shertzer, C. D. Clay, M. B. Genter, M. C. Chames, S. N. Schneider, G. G. Oakley, D. W. Nebert, and T. P. Dalton. (2004) Uncoupling-mediated Generation of Reactive Oxygen by Halogenated Aromatic Hydrocarbons in Mouse Liver Microsomes. Free Radicals in Biology and Medicine, 36:618-631
J. G. Robison, J. S. Elliott, K. Dixon, G. G. Oakley (2004) Replication Protein A (RPA) and the Mre11 Complex Co-localize and Interact at Sites of Stalled Replication Forks. Journal of Biological Chemistry, 279:34802-10.
G. G. Oakley, S. M. Patrick, K Dixon and J. J. Turchi. (2005) DNA Damage Induced Hyper-phosphorylation of Replication Protein A (RPA Effects DNA Replication and DNA Repair via Alterations in DNA Binding Activity and Protein-Protein Interactions). Biochemistry, 44:8438-48)
J. E. Nuss, S. M. Patrick, G. G. Oakley, J. G. Robison, G. M. Alter, K. Dixon, and J. J. Turchi. (2005) Multiple Sites of Phosphorylation on Replication Protein A (RPA) Subunits Contribute to an Altered Affinity for Damaged DNA. Biochemistry, 44:8427-37
Cruet-Hennequart, S., Coyne, S., Glynn, M., Oakley, G. G. and Carty, M.P., (2006) Expression of polymerase  modulates UV-induced DNA damage responses. DNA Repair, 5:491-504

Abstracts:

Oakley, G. G., Patrick, S.M., Turchi J. J. and Dixon, K., Phosphorylation of Replication Protein A (RPA) Induces a Molecular Switch from DNA Replication to DNA Repair. Presented at the 2003 Ataxia-Telangiectasia International Workshop. September 10, 2003, Fraser Island, Australia.
Johnson, B.R., Oakley,G. G.,Robison, J. and Dixon, K.. NBS1 and ATM are involved in the UV-induced formation of replication-dependent double strand breaks. Presented as part of a mini-symposium at the 92nd Annual meeting of the American Association for Cancer Research, AACR Abstract #2220. March 26, 2001, New Orleans, LA.
Vandale, S., Bingham, E., Oakley, G., Roe, A., Mayfield, L., Johnson, B. and Hannah-Hardy, J., Increasing Public Understanding of Issues in Environmental Genetics and Genetic Testing. Presented at the 40th Annual meeting of the Society of Toxicology, SOT Abstract #558. March 26, 2001, San Francisco CA.
Oakley, G. G., Johnson, B.R., Robison, J. and Dixon, K. ATM, NBS1, and RPA are involved in cellular responses to UV-induced DNA damage. Presented at the 2001 Annual Environmental Mutagen Society Meeting, EMS Abstract #159. March 20, 2001, San Diego, CA.