The major focus of my research is to elucidate the biochemical mechanisms involved in the DNA damage repair response, with particular emphasis on environmental UV-induced DNA damage. Cutaneous malignant melanoma (CMM) is the most lethal form of skin cancer, and its incidence has been increasing at an alarming rate in the U.S. and around the world. Exposure to damaging ultraviolet radiation (UV) is clearly a risk factor for the disease, borne out by the recent linkage between tanning bed usage and dramatically increased melanoma incidence in young females. Within our state, melanoma incidence is highest in central Kentucky, directly corresponding to Markey Cancer Center’s catchment area. Thus, the long-term goal of my research is to understand the mechanism (s) of UV carcinogenesis and to develop novel melanoma-preventive strategies.
Individuals with loss-of-function polymorphisms of the melanocortin 1 receptor (MC1R), a Gs-coupled melanocytic surface receptor, have an increased risk of the disease. Inheritance of signaling-defective MC1R is one of the most important genetic risk factors for melanoma, affecting millions of Americans. When bound by agonistic ligands, most notably α-melanocyte stimulating hormone (α-MSH), the MC1R initiates a cascade of UV-protective events mediated by adenylyl cyclase activation and generation of cyclic adenosine monophosphate (cAMP). We are interested in cAMP signaling and how loss-of-function polymorphisms in MC1R are associated with an increased lifetime melanoma risk. We have identified a critical molecular link between MC1R-induced cAMP signaling and the nucleotide excision repair pathway (NER). We recently reported that the critical molecular event linking MC1R signaling to DNA repair is a phosphorylation event of the global cell damage response protein “ataxia telangiectasia and rad3-related protein” (ATR). When cAMP levels are induced either by MSH-MC1R interactions or pharmacologically with adenylyl cyclase activation, cAMP-dependent protein kinase (PKA) becomes activated and phosphorylates ATR on its Serine 435 (S435) residue. This post-translational modification causes ATR to associate with a key DNA repair factor known as xeroderma pigmentosum A protein (XPA). XPA is one of eight core proteins that make up NER, the genome maintenance pathway charged with the removal of UV photoproducts to prevent UV mutagenesis. We found that XPA and ATR-pS435 localize to UV photoproducts in a greatly accelerated and enhanced manner if melanocytes have been stimulated through MC1R signaling or cAMP activation (Figure 1). Our findings suggest that PKA-mediated phosphorylation of ATR at S435 is an important event that dynamically regulates early recruitment and assembly of XPA and possibly other DNA repair proteins to sites of UV damage in order to optimize NER.
Jarrett SG, Wolf Horrell EM, D'Orazio JA. AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair. Nucleic Acids Research. In Press.
Janjetovic Z, Jarrett SG, Lee EF, Duprey C, Reiter RJ, Slominski AT. Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways. Sci Rep. 2017 Apr 28;7(1):1274
Wolf Horrell EM, Jarrett SG, Carter KM, D'Orazio JA. Divergence of cAMP signalling pathways mediating augmented nucleotide excision repair and pigment induction in melanocytes. Exp Dermatol. 2017 Jan 17.
Jarrett SG, Wolf Horrell EM, Boulanger MC, D'Orazio JA. Defining the contribution of MC1R physiological ligands to ATR phosphorylation at Ser435, a predictor of DNA repair in melanocytes. Journal of Investigative Dermatology. 135, 3086-96; 2015.* Featured as a commentary in Journal of Investigative Dermatology: 135, 2918-2921; 2015
Jarrett SG, Wolf Horrell EM, Christian PA, Vanover JC, Boulanger MC, Zou Y, D'Orazio JA. PKA-mediated phosphorylation of ATR promotes recruitment of XPA to UV-induced DNA damage. Molecular Cell. 54:999-1011; 2014.* Featured in the Research Watch section of Cancer Discovery: 4;867; 2014 and as an F1000Prime article recommendation (by David Cortez, PhD; Vanderbilt University).
Janjetovic Z, Nahmias ZP, Hanna S, Jarrett SG, Kim TK, Reiter RJ, Slominski AT. Melatonin and its metabolites ameliorate ultraviolet B-induced damage in human epidermal keratinocytes. Journal of Pineal Research. 57(1):90-102; 2014.
Jarrett SG, Novak M, Harris N, Slominski A and Kaetzel DM. NM23 deficiency promotes metastasis of ultraviolet radiation-induced melanoma in transgenic hepatocyte growth factor mice. Clinical and Experimental Metastasis. 30:25-36; 2013
Jarrett SG, Novak M, Dabernat S, Mellon I, Zhang Q, Harris N, Slominski A and Kaetzel D. Metastasis suppressor NM23-H1 promotes repair of UV-induced DNA damage and suppresses UV-induced melanomagenesis. Cancer Research. 72:133-43, 2012
Jarrett SG, Rohrer B,Perron NR, Beeson C and Boulton ME. Assessment of Mitochondrial Damage in Retinal Cells and Tissues using Quantitative Polymerase Chain Reaction for Mitochondrial DNA Damage and Extracellulur Flux Assay for Mitochondrial Respiration Activity. Methods in Molecular Biology. 935:227-43, 2012
Novak M, Jarrett SG, McCorkle JR, Mellon, I and Kaetzel DM. Multiple mechanisms underlie metastasis suppressor function of NM23-H1 in melanoma. Naunyn Schmiedebergs Arch Pharmacol. 384:433-438; 2011.
Kaetzel DM, McCorkle JR, Novak M, Yang M, Jarrett SG. Potential contributions of antimutator activity to the metastasis suppressor function of NM23-H1. Mol Cell Biochem 329: 161-165; 2009.
Yang M*, Jarrett SG*, Craven R and Kaetzel D. YNK1, the yeast homolog of human metastasis suppressor NM23, is required for repair of UV radiation- and etoposide-induced DNA damage. Mutation Research. 600: 74-78; 2009. *Denotes authors contributed equally to this work.
Jarrett SG, Lin H, Godley B, Boulton M. Mitochondrial DNA damage and its potential role in retinal degeneration. Progress in Retinal and Eye Research. 6: 596-607; 2008.
Jarrett SG, Milder J, Liang, L-P, Patel, M. The ketogenic diet increases mitochondrial glutathione levels. Journal of Neurochemistry. 106: 1044-1051; 2008.
Liang LP, Jarrett SG and Patel M. Status epilepticus-induced iron regulation and relationship to oxidative stress, mitochondria dysfunction and neuronal death. Journal of Neuroscience. 28: 11550-11556; 2009.
Jarrett SG, Liang, L-P, Hellier, JL, Staley, KJ and Patel M. Mitochondrial DNA damage and impaired base excision repair during epileptogenesis. Neurobiology of Disease. 30:130-138; 2008.
Jarrett SG and Boulton M. Poly (ADP-ribose) polymerase offers protection against oxidative and alkylation damage to the nuclear and mitochondrial genomes of the retinal pigment epithelium. Ophthalmic Research. 39:213-223; 2007.
Jarrett SG, Cuenco J and Boulton M. Dietary antioxidants provide differential sub-cellular protection in epithelial cells. Redox Report. 11:144-152; 2006.
Jarrett SG, Albon J and Boulton M. The contribution of DNA repair and antioxidants in determining cell type-specific resistance to oxidative stress. Free Radical Research. 40:1155-1165; 2006.
Godley BF, Shamsi F, Liang F, Jarrett SG, Davies S and Boulton M. Blue light induces mitochondrial DNA damage and free radical production in epithelial cells. Journal of Biological Chemistry. 280:21061-21066; 2005.
Jarrett SG and Boulton M. Antioxidant up-regulation and increased nuclear DNA protection play key roles in adaptation to oxidative stress in epithelial cells. Free Radical Biology and Medicine. 38: 1382- 1391; 2005.
Book Chapter and Reviews
Jarrett SG, Carter KM, D'Orazio JA. Paracrine regulation of melanocyte genomic stability: a focus on nucleotide excision repair. Pigment Cell Melanoma Res. 2017 May;30(3):284-293.
Jarrett SG, D'Orazio JA. Hormonal Regulation of the Repair of UV Photoproducts in Melanocytes by the Melanocortin Signaling Axis. Photochem Photobiol. 2017 Jan;93(1):245-258.
Kaetzel DM, Leonard MK, Cook GS, Novak M, Jarrett SG, Yang X, Belkin AM. Dual functions of NME1 in suppression of cell motility and enhancement of genomic stability in melanoma. Naunyn Schmiedebergs Arch Pharmacol. 388:199-206; 2015.
Jarrett SG, D’Orazio JA. Ctr1-ing BRAF signaling with copper. Pigment Cell Melanoma Research. 27:689-91; 2014; 2014
D’Orazio J, Jarrett SG, Amaro-Ortiz A and Scott T. UV Radiation and the Skin. International Journal of Molecular Science. 14:1222-48; 2013
Jarrett SG, Amaro-Ortiz A, Tucker J and D’Orazio J. The Melanocortin-1 Receptor: A Key Melanoma Risk Determinant and a Critical Regulator of the UV DNA Damage Repair Response. In: Skin Pigmentation: Genetics, Geographic Variation and Disorders, Nova 2013.
D’Orazio JA, Jarrett SG, Marsch A, Lagrew J and Cleary L. Melanoma-Epidemiology, Genetics and Risk factors. In: Recent Advances in the Biology, Therapy and Management of Melanoma, Intech, 2012
Jarrett SG and Boulton M. Consequences of oxidative stress in age-related macular degeneration. Molecular Aspects of Medicine. 33: 399-417; 2012
Jarrett SG, Lewin A and Boulton ME. The Role of Mitochondria Oxidative Stress in Retinal Dysfunction. In: Studies on Retinal and Choroidal Disorders Stratton, Hauswirth and Gardener (eds), Springer Press; 2011
Jarrett SG, Lewin, A, Boulton M. Mitochondrial DNA damage in age-related and inherited disorders. Ophthalmic Res. 44:179-90; 2010.