Gregory G. Oakley, PhD

Dr. Oakley

Associate Professor

Department of Oral Biology

Contact Information

Room 1402, UNMC College of Dentistry
4000 East Campus Loop South
Lincoln, NE 68583-0740
402-472-3519

Education

Teaching Responsibilities 
  • Course Instructor, Biochemistry for Dental Students (ORBI 545)
  • Course Instructor, A Review of Biomedical Sciences (ORBI 571)
  • Course Instructor, General Pharmacology (ORBI 639)
  • Course Instructor, Oral Pharmacology (ORBI 653)
  • Course Instructor, Advanced Dental Pharmacology (OBIO 862)
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 
  • UNMC Buffett Cancer Center, “FOXMI/RHN01: A novel oncogenic module and therapeutic target in high grade serous ovarian cancer,” Co-Principal Investigator, $50,000, 4/2017 - 3/2018
  • NRI, “Targeting the RPA:RAD52 complex for cancer therapeutics,” Principal Investigator, $100,000, 7/2014 - 6/2016
  • NIH/NIGMS, “Biochemical investigation of oxidative DNA damage response,” Co-Principal Investigator, $50,000, 3/2014 - 7/2015
  • American Cancer Society Research Scholar Grant, “RPA phosphorylation and the cellular response to DNA damage”, Principal Investigator, $720,000, 1/2010 - 12/2013
  • NIH, UNMC Nebraska Center for Cellular Signaling, Principal Investigator: M.J. Wheelock; Project Leader: G. Oakley; $1,077,167 (project funding), 12/2005 - 6/2009
  • American Cancer Society Ohio Division Pilot Research, “Mre11 and RPA protein-protein interactions in DNA damage response pathways,”  Principal Investigator, $30,000, 9/2004 - 8/2006
Selected Publications 
  • Rector J, Kapil S, Treude KJ, Kumm P, Glanzer JG, Byrne BM, Liu S, Smith LM, DiMaio DJ, Giannini P, Smith RB, Oakley GG. S4S8-RPA phosphorylation as an indicator of cancer progression in oral squamous cell carcinomas. Oncotarget 8:9243-9250, 2016.
  • Glanzer JG, Endres JL, Byrne BM, Liu S, Bayles KW, Oakley GG. Identification of inhibitors for single-stranded DNA-binding proteins in eubacteria. Journal of Antimicrobial Chemotherapy 71:3432-3440, 2016.
  • Glanzer JG, Byrne BM, McCoy AM, James BJ, Frank JD, Oakley GG. In silico and in vitro methods to identify ebola virus VP35-dsRNA inhibitors. Bioorganic and Medicinal Chemistry 24:5388-5392, 2016.
  • Kijas AW, Lim YC, Bolderson E, Cerosaletti K, Gatei M, Jakob B, Tobias F, Tacher-Scholz G, Gueven N, Oakley G, Concannon P, Wolvetang E, Khanna KK, Wiesmuller L, Lavin MF.  ATM-dependent phosphorylation of MRE11 controls extent of resection during homology directed repair by signalling through Exonuclease 1. Nucleic Acids Res 43:8352-8367 2015.
  • Ghospurkat PF, Wilson TM, Liu S, Herauf A, Steffes J, Mueller EN, Oakley GG, Haring SJ. Phosphorylation and cellular function of the human Rpa2 N-terminus in the budding yeast Saccharomyces cerevisiae. Exp Cell Res 33:183-199, 2015
  • Glanzer, J.G., Liu, S., Wang, L., Mosel, A., Peng, A., and Oakley, G.G. RPA inhibition increases replication stress and suppresses tumor growth. Cancer Research 74:5165-5172, 2014.
  • Borgstahl, G.E., Brader, K., Mosel, A., Liu, S., Kremmer, E., Goettsch, K.A., Kolar, C., Nasheuer, H.P., and Oakley, G.G. Interplay of DNA damage and cell cycle signaling at the level of human replication protein A. DNA Repair 21:12-23, 2014.
  • Ashley, A.K., Shrivastav, M., Nie, J., Amerin, C., Troksa, K., Glanzer, J.G., Liu, S., Opiyo, S.O., Dimitrova, D.D., Le, P., Sishc, B., Bailey, S.M., Oakley, G.G., and Nickoloff, J.A. DNA-PK phosphorylation of RPA32 Ser4/Ser8 regulates replication stress checkpoint activation, fork restart, homologous recombination and mitotic catastrophe. DNA Repair 21:131-139, 2014.
  • Glanzer, J.G., Carnes, K.A., Soto, P., Liu, S., Parkhurst, L.J., and Oakley, G.G. A small molecule directly inhibits the p53 transactivation domain from binding to replication protein A. Nucleic Acids Research 41:2047-2059, 2013.
  • Liu, S., Opiyo, S.O., Manthey, K., Glanzer, J.G., Ashley, A.K., Amerin, C., Troksa, K., Shrivastav, M., Nickoloff, J.A. and Oakley, G.G. Distinct roles for DNA-PK, ATM and ATR in RPA phosphorylation and checkpoint activation in response to replication stress. Nucleic Acids Research 40: 10780-10794, 2012
  • Wang, L., Mosel, A.J., Oakley, G.G. and Peng, A. Deficient DNA damage signaling leads to chemoresistance to cisplatin in oral cancer. Molecular Cancer Therapeutics 11:2401-2409, 2012.
  • Zhu, X., Ozturk, F., Liu, C., Oakley, G.G. and Nawshad, A. Transforming growth factor-β activates c-Myc to promote palatal growth. Journal of Cellular Biochemistry 113:3069-3085, 2012.
  • Glanzer, J.G., Liu, S., and Oakley, G.G.  Small molecule inhibitor of the RPA70 N-terminal protein interaction domain discovered using in silico and in vitro methods. Bioorganic Medicinal Chemistry 19:2589-2595, 2011.
  • Bharadwa, A.G., Goodrich, N.P., McAtee, C.O., Haferbier, K., Oakley, G.G., Wahl, J.K. 3rd, and Simpson, M.A. Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling. Experimental Cell Research 317:1214-1225, 2011.
  • Oakley, G.G. and Patrick, S.M. Replication Protein A: Directing traffic at the intersection of replication and repair. Frontiers in Bioscience 15:883-900, 2010. (Invited Review)
  • Liyanage, N. P. M., Manthey, K. C., Dassanayake, R. P., Kuszynski, C. A., Oakley, G. G., and Duhamel, G. E. Helicobacter hepaticus Cytolethal distending toxin causes cell death in intestinal epithelial cells via mitochondrial apoptotic pathway. Helicobacter 15:98-107, 2010.
  • Manthey, K.C., Glanzer, J.D., Dimitrova, D. and G.G. Oakley. Hyperphosphorylation of RPA predicts cisplatin and etoposide resistance in squamous cell head and neck carcinoma cell lines. Head and Neck 32:636-645, 2010.
  • Oakley, G.G., Tillison, K., Opiyo, S., Glanzer, J.G., Horn, J., and Patrick, S.M. Physical interaction between replication Protein A (RPA) and MRN: Involvement of RPA phosphorylation and RPA70N basic cleft. Biochemistry 48:7473-81, 2009.
  • Deng, X., Prakash, A.., Dhar, K., Baia, G.S., Kolar, C., Oakley, G.G., and Borgstahl, G.E.O. Human replication Protein A, Rad52, ssDNA complex: Stoichiometry and evidence for strand transfer regulation by phosphorylation. Biochemistry 48:6633-43, 2009.
  • Bharadwaj, A.G., Kovar, J.L., Loughman, E., Elowsky, C. Oakley, G.G., and Simpson, M.A. Spontaneous metastasis of prostate cancer is promoted by excess hyaluronan synthesis and processing. American Journal of Pathology 174:1027, 2009.
  • Manthey, K.C., Opiyo, S., Glanzer, J.G., Dimitrova, D., Elliott, J., and Oakley, G.G. NBS1 mediates ATR-dependent RPA hyperphosphorylation following replication-fork stall and collapse.  J of Cell Science 120: 4221-4229, 2007.
  • Cruet-Hennequart, S., Coyne, S., Glynn, M., Oakley, G. G. and Carty, M.P., (2006) Expression of polymerase eta modulates UV-induced DNA damage responses. DNA Repair 5:491-504.
  • 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.
  • 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, 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.
  • 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, 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.
  • 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.