Room 1402, UNMC College of Dentistry
4000 East Campus Loop South
Lincoln, NE 68583-0740
- Bachelor of Pharmacy, University of Kentucky
- BS, Biology, University of Kentucky
- PhD, Toxicology, University of Kentucky
- Course Director - ORBI 401/Introduction to Pharmacology
- Course Director - ORBI 639/General Pharmacology
- Course Director - ORBI 653/Oral Pharmacology
- Course Director - ORBI 862/Advanced Dental Pharmacology
- Course Director - OB 970/Graduate Student Seminar Series
A major interest of my laboratory is the function of RPA phosphorylation in response to DNA damage. My laboratory was the first to provide definitive evidence that replication stress-induced phosphorylation of RPA is required for ATR signaling to Chk1 and activation of a G2/M checkpoint arrest. Cells lacking efficient phosphorylation of RPA displayed a hyper-recombination phenotype in addition to defects in replication re-start and late origin firing. Combined our results show that ATR and ATM signaling through RPA promote genome stability and cell survival in response to replication stress.
Discovering the cross-talk between the ATM and ATR signaling pathways, I built upon that interest analyzing the Mre11/Rad50/Nbs1 (MRN) complex involvement in the replication stress response. Up to that time, the MRN complex was primarily known as a complex upstream and downstream of ATM in the ATM response to DNA double-strand breaks. I identified a protein-protein interaction between RPA and Mre11 and RPA and Nbs1 of the MRN complex in response to replication stress. These interactions are important for proper recovery of collapsed replication forks that suggested a MRN dependent mode of activation of the ATR signaling pathway.
A natural progression of my interest in RPA is the identification of small molecule inhibitors of the replication stress-induced protein-protein interactions (PPI) of RPA. My laboratory identified the first chemical compound, fumaropimaric acid, which binds to the N-terminal domain of the large subunit of RPA, RPA70, and inhibits critical RPA protein-protein interactions required for activation of the ATR signaling pathway. The identification of fumaropimaric acid was significant, as it was the first PPI inhibitor of RPA70 with replication stress response proteins. This discovery paved the way, despite the challenging nature of identifying specific small molecule inhibitors of PPIs, for future discoveries by our laboratory and others. Using a similar high throughput approach, we identified HAMNO, (now sold by Sigma-Aldrich) as an RPA PPI inhibitor. This was the first RPA inhibitor to exhibit an effect in both cells and an in vivo tumor model. HAMNO and others newly discovered candidate therapeutics for cancer treatment act synergistically with present day chemotherapeutics in slowing tumor grow in a mouse model and provide selectivity in cancer cells by targeting their differential response to replication stress. As we continue this research, we are in position to make a substantial contribution to anticancer treatment through the identification and optimization of lead structures that target and inhibit the pathogenesis of cancers with a replication stress component.
- 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
- Byrne BM and Oakley GG. Replication protein A, the laxative that keeps DNA regular: The importance of RPA phosphorylation in maintaining genome stability. Semin Cell Dev Biol. 2019, 86:112-120.
- Simhadri S, Vincelli G, Huo Y, Misenko S, Foo TK, Ahlskog J, Sorensen CS, Oakley GG, Ganesan S, Bunting SF, Xia B. PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response. Oncogene 2019, 38:1585-1596.
- FeiFei Wang, Songli Zhu, Chunling Li, Weidong Wang, Gregory G. Oakley and Aimin Peng, Protein interactomes of protein phosphatase 2A B55 regulatory subunits reveal B55- mediated regulation of replication protein A under replication stress. Sci Rep. 2018 Feb 8;8(1):2683. doi: 10.1038/s41598-018-21040-6.
- FeiFei Wang, Songli Zhu, Chunling Li, Weidong Wang, Gregory G. Oakley and Aimin Peng. Protein interactomes of protein phosphatase 2A B55 regulatory subunits reveal B55- mediated regulation of replication protein A under replication stress. Scientific Reports, 8:2683-2692, 2018.
- 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.