Sarah Graham Kenan Professor of Biochemistry & Biophysics
MD: Istanbul University
PhD: University of Texas
- NC researchers find final pieces to the circadian clock puzzle
- Aziz Sancar's paper "Mechanism of Photosignaling by Drosophila Cryptochrome:Role of the Redox Status of the Flavin Chromophore" selected "Paper of the Week" in the Feb. 2014 issue of the Journal of Biological Chemistry.
- Shobhan Gaddameedhi received the 2013 Postdoctoral Award for Excellence in Research at UNC.
- Shobhan Gaddameedhi places third at the Oliver Smithies Nobel Symposium poster competition
- Nuri Ozturk receives a 2011 Postdoctoral Research Award
- Shobhan Gaddameedhi receives a 2011 CEHS Pilot Grant Award
- Jin Hyup Lee receives a 2011 Graduate School GEAB Impact Award
- Sancar featured in cover story of major Turkish newspaper (Cumhuriyet): "Kanser tanı ve tedavisinde biyolojik saatin önemi"
- Aziz Sancar receives a 2009 Distinguished Alumni Award from University of Texas, Dallas
- Tinkering with the circadian clock can suppress cancer growth (Video)
- UNC study supports the role of circadian clock in chemotherapy
- Time of Day Can Be Critical in Chemotherapy (NIH Research Matters)
We are studying the molecular mechanism of nucleotide excision repair in humans. This is a general DNA repair system that repairs all base lesions including the carcinogenic lesions induced by the main environmental carcinogens sunlight and cigarette smoke. Our lab was the first to reconstitute the excision nuclease in a defined system. Our current work on excision repair aims to understand the structural and kinetic factors that enable the human excision nuclease to remove virtually infinite types of base lesions and to define the interconnections between DNA excision repair, the DNA damage checkpoints, and the circadian clock.
DNA Damage Checkpoints
DNA damage checkpoints are biochemical pathways that transiently block cell cycle progression while the DNA contains damage. Checkpoints prevent genomic instability, cancer, and death in multicellular organisms. The DNA damage checkpoints, like other signal transduction pathways, have four components: damage sensors, mediators, signal transducers and effectors. The goal of our research is to purify the human checkpoint proteins, characterize these proteins biochemically, and reconstitute the DNA damage checkpoint in vitro. We have already established an in vitro system that recapitulates some of the key features of the human DNA damage checkpoint response to base damage. Abnormal checkpoint response to DNA damage is a universal feature of cancers, and biochemical characterization of the checkpoint response should aid in developing new approaches to cancer chemotherapy.
Cryptochrome and Regulation of the Biological Clock
Circadian rhythm is the oscillation in physiology and behavior of organisms with approximately 24-hour periodicity. The circadian clock is synchronized to the daily solar cycle by light. We have discovered that a flavoprotein called cryptochrome, closely related to the light-dependent DNA repair enzyme photolyase, regulates the mammalian circadian clock by light-independent and light-dependent mechanisms. Currently, we are investigating the action mechanism of cryptochrome using biophysical methods including femtochemistry and biochemical methods. In addition, we are investigating the connection between the circadian cycle and DNA repair and how disruption of the circadian cycle might affect the susceptibility of mice and humans to cancers.
Interconnection between the Circadian Clock and DNA Excision Repair
- Ozturk N, Selby CP, Zhong D, Sancar A. (2014) Mechanism of Photosignaling by Drosophila Cryptochrome:Role of the Redox Status of the Flavin Chromophore. J Biol Chem. 289: 4634-4642
- Annayev Y, Adar S, Chiou YY, Lieb J, Sancar A, Ye R. (2014) Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor that Modulates Circadian Gene Expression. J Biol Chem. 289: 5013-5024
- Lindsey-Boltz LA, Kemp MG, Reardon JT, Derocco V, Iyer RR, Modrich P, Sancar A. (2014) Coupling of Human DNA Excision Repair and ATR-mediated DNA Damage Checkpoint in a Defined In Vitro System. J Biol Chem. 289: 5074-5082
- Choi JH, Gaddameedhi S, Kim SY, Hu J, Kemp MG, Sancar A. Highly specific and sensitive method for measuring nucleotide excision repair kinetics of ultraviolet photoproducts in human cells. Nucleic Acids Res. 2013 Nov 22, in press.
- Liu Z, Tan C, Guo X, Li J, Wang L, Sancar A, Zhong D. Determining complete electron flow in the cofactor photoreduction of oxidized photolyase. Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):12966-71.
- Liu Z, Zhang M, Guo X, Tan C, Li J, Wang L, Sancar A, Zhong D. Dynamic determination of the functional state in photolyase and the implication for cryptochrome. Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):12972-7.
- Ozkan-Dagliyan I, Chiou YY, Ye R, Hassan BH, Ozturk N, Sancar A. Formation of Arabidopsis Cryptochrome 2 Photobodies in Mammalian Nuclei: Application As An Optogenetic DNA Damage Checkpoint Switch. J Biol Chem. 2013 Aug 9;288(32):23244-51.
- Hu J, Choi JH, Gaddameedhi S, Kemp MG, Reardon JT, Sancar A. Nucleotide excision repair in human cells: fate of the excised oligonucleotide carrying DNA damage in vivo. J Biol Chem. 2013 Jul 19;288(29):20918-26.
- Hassan BH, Lindsey-Boltz LA, Kemp MG, Sancar A. Direct role for the replication protein treslin (Ticrr) in the ATR kinase-mediated checkpoint response. J Biol Chem. 2013 Jun 28;288(26):18903-10.
- Ozturk N, VanVickle-Chavez SJ, Akileswaran L, Van Gelder RN, Sancar A. Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila Cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex. Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):4980-5.
- Lee JH, Gaddameedhi S, Ozturk N, Ye R, Sancar A. DNA damage-specific control of cell death by cryptochrome in p53-mutant ras-transformed cells. Cancer Res. 2013 Jan 15;73(2):785-91.
- Lindsey-Boltz LA, Reardon JT, Wold MS, Sancar A. In vitro analysis of the role of replication protein A (RPA) and RPA phosphorylation in ATR-mediated checkpoint signaling. J Biol Chem. 2012 Oct 19;287(43):36123-31.
- Gaddameedhi S, Reardon JT, Ye R, Ozturk N, Sancar A. Effect of circadian clock mutations on DNA damage response in mammalian cells. Cell Cycle. 2012 Sep 15;11(18):3481-91.
- Kemp MG, Sancar A. DNA excision repair: where do all the dimers go? Cell Cycle. 2012 Aug 15;11(16):2997-3002
- Kemp MG, Reardon JT, Lindsey-Boltz LA, Sancar A. Mechanism of release and fate of excised oligonucleotides during nucleotide excision repair. J Biol Chem. 2012 Jun 29;287(27):22889-99.
- Liu Z, Guo X, Tan C, Li J, Kao YT, Wang L, Sancar A, Zhong D. Electron tunneling pathways and role of adenine in repair of cyclobutane pyrimidine dimer by DNA photolyase. J Am Chem Soc. 2012 May 16;134(19):8104-14.
- Rivera AS, Ozturk N, Fahey B, Plachetzki DC, Degnan BM, Sancar A, Oakley TH. Blue-light-receptive cryptochrome is expressed in a sponge eye lacking neurons and opsin. J Exp Biol. 2012 Apr 15;215(Pt 8):1278-86.
- Selby CP, Sancar A. The second chromophore in Drosophila photolyase/cryptochrome family photoreceptors. Biochemistry. 2012 Jan 0;51(1):167-71.
- Gaddameedhi S, Selby CP, Kaufmann WK, Smart RC, Sancar A. Control of skin cancer by the circadian rhythm. Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18790-5.
- Yilmaz S, Sancar A, Kemp MG. Multiple ATR-Chk1 pathway proteins preferentially associate with checkpoint-inducing DNA substrates. PLoS One. 2011;6(7):e22986.
- Lee JH, Sancar A. Regulation of apoptosis by the circadian clock through NF-kappaB signaling. Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12036-41.
- Lee JH, Sancar A. Circadian clock disruption improves the efficacy of chemotherapy through p73-mediated apoptosis. Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):10668-72.
- Ye R, Selby CP, Ozturk N, Annayev Y, Sancar A. Biochemical analysis of the canonical model for the mammalian circadian clock. J Biol Chem. 2011 Jul 22;286(29):25891-902.
- Lindsey-Boltz LA, Sancar A. Tethering DNA damage checkpoint mediator proteins topoisomerase IIbeta-binding protein 1 (TopBP1) and Claspin to DNA activates ataxia-telangiectasia mutated and RAD3-related (ATR) phosphorylation of checkpoint kinase 1 (Chk1). J Biol Chem. 2011 Jun 3;286(22):19229-36.
- Kemp MG, Lindsey-Boltz LA, Sancar A. The DNA damage response kinases DNA-dependent protein kinase (DNA-PK) and ataxia telangiectasia mutated (ATM) Are stimulated by bulky adduct-containing DNA. J Biol Chem. 2011 Jun 3;286(22):19237-46.
- Kang TH, Reardon JT, Sancar A. Regulation of nucleotide excision repair activity by transcriptional and post-transcriptional control of the XPA protein. Nucleic Acids Res. 2011 Apr;39(8):3176-87.
- Ozturk N, Selby CP, Annayev Y, Zhong D, Sancar A. Reaction mechanism of Drosophila cryptochrome. Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):516-21.
- Gaddameedhi S, Sancar A. Melanoma and DNA damage from a distance (farstander effect). Pigment Cell Melanoma Res. 2011 Feb;24(1):3-4.
- Li J, Liu Z, Tan C, Guo X, Wang L, Sancar A, Zhong D. Dynamics and mechanism of repair of ultraviolet-induced (6-4) photoproduct by photolyase. Nature. 2010 Aug 12;466(7308):887-890.
- Choi JH, Lindsey-Boltz LA, Kemp M, Mason AC, Wold MS, Sancar A. Reconstitution of RPA-covered single-stranded DNA-activated ATR-Chk1 signaling. Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13660-5.
- Gaddameedhi S, Kemp MG, Reardon JT, Shields JM, Smith-Roe SL, Kaufmann WK, Sancar A. Similar nucleotide excision repair capacity in melanocytes and melanoma cells. Cancer Res. 2010 Jun 15;70(12):4922-30.
- Kang TH, Lindsey-Boltz LA, Reardon JT, Sancar A. Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):4890-5.
- Kemp MG, Akan Z, Yilmaz S, Grillo M, Smith-Roe SL, Kang TH, Cordeiro-Stone M, Kaufmann WK, Abraham RT, Sancar A, Unsal-Kaçmaz K. Tipin-replication protein A interaction mediates Chk1 phosphorylation by ATR in response to genotoxic stress. J Biol Chem. 2010 May 28;285(22):16562-71.
- Sancar A, Lindsey-Boltz LA, Kang TH, Reardon JT, Lee JH, Ozturk N. Circadian clock control of the cellular response to DNA damage. FEBS Lett. 2010 Jun 18;584(12):2618-25.
120 Mason Farm Rd,
Campus Box # 7260
3093 Genetic Medicine
Chapel Hill, NC 27599
Lab Rooms: 3073 Genetic Medicine