Sarah Graham Kenan Professor of Biochemistry and Biophysics
Adjunct Appointment in Biology
(PhD – University of Texas; MD – Istanbul University)
HONORS AND AWARDS:
- 1969 MD, Summa Cum Laude (1st in class of 625)
- 1977 PhD, University of Texas at Dallas
- 1984 NSF Presidential Young Investigator Award
- 1995 NIH MERIT Award
- 2004 American Academy of Arts and Sciences
- 2005 National Academy of Sciences, USA
- 2006 Turkish Academy of Sciences
- 2007 Turkish Koç Award
- 2009 Univ. of Texas at Dallas Distinguished Alumni Award
- 2014 Distinguished Visiting Professor – Academia Sinica
- 2015 Nobel Prize in Chemistry
- 2016 TWESCO International Turkish Academy – Gold Medal at UN
- 2016 ASBMB American Society for Biochemistry & Molecular Biology – Bert and Natalie Vallee Award
- 2016 O. Max Gardner Award – highest honor by UNC Board of Governors
- 2016 Carnegie Corporation’s Immigrant of the Year
- 2016 North Carolina Award – the highest civilian honor given by the state
- 2016 National Academy of Medicine
- In addition, many awards and honorary doctorate degrees
Our lab works on three interrelated subjects: (1) DNA Repair Enzymology and Genomics; (2) Mammalian Circadian Clock; (3) Control of DNA Repair by the Circadian Clock.
DNA Repair Enzymology and Genomics
Mammalian Circadian Clock
The circadian clock is the internal timekeeping system that controls cyclic changes in physiology and behavior to prepare the organism for the unique challenges of the solar day. In mice and humans the circadian rhythm at the organismal level is generated by a molecular clock of periodicity of ~24 hrs. The molecular clock consists of a transcription-translation feedback loop (TTFL) in which the heterodimeric transcriptional activator CLOCK-BMAL1 promotes transcription of transcriptional repressors, CRY (Cryptochrome) and PER (Period) which counter the activity of CLOCK-BMAL1 as shown in Fig. 3A. Our group discovered that CRY is a core human clock protein and that it mediates repression by two mechanisms (Fig. 3B,C): In one CRY binds to the CLOCK-BMAL1 complex on DNA and blocks its interaction with the transcription machinery.
In the second mode of repression, the co-repressor PER displaces the entire activator complex from the promoter in a CRY-dependent manner. Our research has provided a mechanistic basic for how this dual repression mechanism confers precision and resilience and, at the same time, flexibility and adaptability to the signaling pathways and networks and therefore influences physio-pathologic conditions ranging from sleep regulation and jetlag to metabolic syndrome to cancer. We discovered that the circadian clock regulates nucleotide excision repair and hence the susceptibility to UV-induced skin cancer as a function of time of the day of exposure to light. Because excision repair is also the main repair mechanism for removing DNA lesions from the genome that are generated by the anti-cancer drug cisplatin, we are currently working at translating our finding of clock-excision repair connection to develop improved chemotherapy regimens.
Control of DNA Repair by the Circadian Clock
We discovered that the circadian clock controls nucleotide excision repair in mammalian organisms. We wish to apply this finding for cancer prevention and treatment because excision repair removes DNA damage caused by carcinogens as well as damage caused by anticancer drugs. We are using mice as the model organism for these studies. We found that excision repair of carcinogenic UV damage in mice is low at early morning hours and reaches its highest level in the evening. As a consequence, mice exposed to carcinogenic UVB light in morning are 4-times more likely to develop invasive skin cancer than mice exposed to the same UVB dose in the evening (Fig. 3A). These findings should have implications for the optimum time for human sun exposure. To determine the effect of the circadian clock on the repair of DNA damage caused by the anticancer drug cisplatin, we injected cisplatin into mice at 4 hour intervals for a period of one day and analyzed the repair of Platinum-DNA adducts over the course of the day genome-wide and at single nucleotide resolution. We found that the repair of Pt-DNA adducts is controlled by two circadian programs in mouse tissue: (1) The clock controls transcription of 1500-2000 genes with expression maxima of different genes spread over the entire day, but with the majority peaking at pre-dawn and pre-dusk. Because transcription stimulates repair of adducts in the transcribed strand (TS), the TS of circadian-controlled genes are repaired at times of day specific for each gene with prominent peaks at pre-dawn and pre-dusk (Fig. 3B). (2) The clock controls expression of the XPA protein and therefore of excision repair activity which peaks at ZT8-10 (ZT=0 is the time when light is turned on, ZT=12 is the time light is turned off under 12h light: 12h dark conditions). Because the basal repair activity has rhythmicity, the repair of Pt-DNA adducts in the regions of the genome that are not transcribed (the nontranscribed strand (NTS) of transcribed genes, both strands of non-transcribed genes, and intergenic regions) peak at ZT8-10. As a consequence of these two circadian programs, in many circadian-controlled genes the peak and trough repair times for TS and NTS are different, and sometimes anti-phase. Cisplatin is the most commonly used chemotherapeutic drug for treating solid tumors. However, the usefulness of this important drug is limited due of its toxicity and primary acquired resistance by cancer cells. Frequently, biochemical pathways of cancer cells are out of synchrony with those in normal tissues, and these are indications that the circadian clock is “broken” in cancerous tissue. We aim to take advantage of our data regarding orderly repair in normal tissue compared to arrhythmic repair in cancer to develop cisplatin administration regiments (Chronochemotherapy) to improve the efficacy and reduce side effects of cisplatin therapy.
- Yang Y, Liu Z, Selby CP, Sancar A. Long-term, genome-wide kinetic analysis of the effect of the circadian clock and transcription on the repair of cisplatin-DNA adducts in the mouse liver. J Biol Chem. 2019 Jun 19. pii: jbc.RA119.009579. doi: 10.1074/jbc.RA119.009579. [Epub ahead of print] PMID:31217280.
- Phelps CA, Lindsey-Boltz L, Sancar A, Mu D. (2019) Mechanistic Study of TTF-1 Modulation of Cellular Sensitivity to Cisplatin.Sci Rep. 9(1):7990. doi: 10.1038/s41598-019-44549-w. PMID:31142791.
- Li W, Liu W, Kakoki A, Wang R, Adebali O, Jiang Y, Sancar A. (2019) Nucleotide excision repair capacity increases during differentiation of human embryonic carcinoma cells into neurons and muscle cells. J Biol Chem. 294(15):5914-5922. PMID: 30808711.
- Yimit A, Adebali O, Sancar A, Jiang Y (2019) Differential damage and repair of DNA-adducts induced by anti-cancer drug cisplatin across mouse organs. Nature Communications 10(1), 309.
- Hu J, Li W, Adebali O, Yang Y, Oztas O, Selby CP, Sancar A. (2019) Genome-wide mapping of nucleotide excision repair with XR-seq. Nature Protocols 14(1):248-282. PMID: 30552409.
- Yang Y, Hu J, Selby CP, Li W, Yimit A, Jiang Y, Sancar A. (2019) Single-nucleotide resolution analysis of nucleotide excision repair of ribosomal DNA in humans and mice. J Biol Chem. 294(1):210-217. doi: 10.1074/jbc.RA118.006121. PMID: 30413533.
- Wang X, Jing C, Selby CP, Chiou YY, Yang Y, Wu W, Sancar A, Wang J. (2018) Comparative properties and functions of type 2 and type 4 pigeon cryptochromes. Cell Mol Life Sci. 75(24):4629-4641. doi: 10.1007/s00018-018-2920-y. PMID: 30264181.
- Yang Y, Adebali O, Wu G, Selby CP, Chiou YY, Rashid N, Hu J, Hogenesch JB, Sancar A. (2018) Cisplatin-DNA adduct repair of transcribed genes is controlled by two circadian programs in mouse tissues. Proceedings of the National Academy of Sciences of the United States of America 115(21):E4777-E4785. PMID: 30413533.
- Li W, Adebali O, Yang Y, Selby CP, Sancar A (2018) Single-nucleotide resolution dynamic repair maps of UV damage in Saccharomyces cerevisiae genome. Proceedings of the National Academy of Sciences of the United States of America 115(15):E3408-E3415.
- Oztas O, Selby CP, Sancar A, Adebali O. (2018) Genome-wide excision repair in Arabidopsis is coupled to transcription and reflects circadian gene expression patterns. Nature Communications 9(1):1503. doi: 10.1038/s41467-018-03922-5. PMID: 29666379.
- Chiou YY, Hu J, Sancar A, Selby CP. (2017) RNA polymerase II is released from the DNA template during transcription-coupled repair in mammalian cells. J Biol Chem. pii: jbc.RA117.000971. doi: 10.1074/jbc.RA117.000971. [Epub ahead of print] PMID: 29282293.
- Hughes ME, Abruzzi KC, Allada R, Anafi R, Arpat AB, Asher G, Baldi P, de Bekker C, Bell-Pedersen D, Blau J, Brown S, Ceriani MF, Chen Z, Chiu JC, Cox J, Crowell AM, DeBruyne JP, Dijk DJ, DiTacchio L, Doyle FJ, Duffield GE, Dunlap JC, Eckel-Mahan K, Esser KA, FitzGerald GA, Forger DB, Francey LJ, Fu YH, Gachon F, Gatfield D, de Goede P, Golden SS, Green C, Harer J, Harmer S, Haspel J, Hastings MH, Herzel H, Herzog ED, Hoffmann C, Hong C, Hughey JJ, Hurley JM, de la Iglesia HO, Johnson C, Kay SA, Koike N, Kornacker K, Kramer A, Lamia K, Leise T, Lewis SA, Li J, Li X, Liu AC, Loros JJ, Martino TA, Menet JS, Merrow M, Millar AJ, Mockler T, Naef F, Nagoshi E, Nitabach MN, Olmedo M, Nusinow DA, Ptáček LJ, Rand D, Reddy AB, Robles MS, Roenneberg T, Rosbash M, Ruben MD, Rund SSC, Sancar A, Sassone-Corsi P, Sehgal A, Sherrill-Mix S, Skene DJ, Storch KF, Takahashi JS, Ueda HR, Wang H, Weitz C, Westermark PO, Wijnen H, Xu Y, Wu G, Yoo SH, Young M, Zhang EE, Zielinski T, Hogenesch JB (2017) Guidelines for Genome-Scale Analysis of Biological Rhythms. Journal of biological rhythms 32(5), 380-393.
- Adebali O, Sancar A, Selby CP (2017) Mfd translocase is necessary and sufficient for transcription-coupled repair in Escherichia coli.
The Journal of biological chemistry 292(45), 18386-18391.
- Hu J, Selby CP, Adar S, Adebali O, Sancar A. (2017) Molecular mechanisms and genomic maps of DNA excision repair in E.coli and humans. J Biol Chem.R117.807453. doi: 10.1074/jbc.R117.807453. (in press).
- Hu J, Adebali O, Adar S, Sancar A. (2017) Dynamic maps of UV damage formation and repair for the human genome. Proc Natl Acad Sci U S A. 114(26):6758-6763. doi: 10.1073/pnas.1706522114.
- Li W, Hu J, Adebali O, Adar S, Yang Y, Chiou YY, Sancar A. (2017) Human genome-wide repair map of DNA damage caused by the cigarette smoke carcinogen benzo[a]pyrene. Proc Natl Acad Sci U S A. 114(26):6752-6757. doi: 10.1073/pnas.1706021114. PMID: 28607059.
- Li W, Hu J, Adebali O, Adar S, Yang Y, Chiou YY, Sancar A. (2017) Human genome-wide repair map of DNA damage caused by the cigarette smoke carcinogen benzo[a]pyrene. Proc Natl Acad Sci U S A. 114(26):6752-6757. doi: 10.1073/pnas.1706021114.
- Krishnaiah SY, Wu G, Altman BJ, Growe J, Rhoades SD, Coldren F, Venkataraman A, Olarerin-George AO, Francey LJ, Mukherjee S, Girish S, Selby CP, Cal S, Er U, Sianati B, Sengupta A, Anafi RC, Kavakli IH, Sancar A, Baur JA, Dang CV, Hogenesch JB, Weljie AM. (2017) Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism. Cell Metab. 4;25(4):961-974.e4. doi: 10.1016/j.cmet.2017.03.019.
- Adebali, O, Chiou YY, Hu J, Sancar A, Selby CP. (2017) Genome-wide transcription-coupled repair in Escherichia coli is mediated by the Mfd translocase. Proc Natl Acad Sci U S A. 14;114(11):2116-2125. PMID: 28167766.Zhang M, Wang L, Shu S, Sancar A, Zhong D. (2016) Bifurcating electron-transfer pathways in DNA photolyases determine the repair quantum yield. Science. 14;354(6309):209-213.
- Zhang M, Wang L, Shu S, Sancar A, Zhong D. (2016) Bifurcating electron-transfer pathways in DNA photolyases determine the repair quantum yield. Science. 354(6309):209-213. PMID: 27738168.
- Hu J, Lieb JD, Sancar A, Adar S. (2016) Cisplatin DNA damage and repair maps of the human genome at single-nucleotide resolution. Proc Natl Acad Sci U S A. 11;113(41):11507-11512.
- Chiou YY, Yang Y, Rashid N, Ye R, Selby CP, Sancar A. (2016) Mammalian Period represses and de-represses transcription by displacing CLOCK-BMAL1 from promoters in a Cryptochrome-dependent manner. Proc Natl Acad Sci U S A. 11;113(41):E6072-E6079.
- Sancar A. (2016) Mechanisms of DNA Repair by Photolyase and Excision Nuclease (Nobel Lecture). Angew Chem Int Ed Engl. 18;55(30):8502-27. doi: 10.1002/anie.201601524.
- Jang H, Lee GY, Selby C, Lee G, Jeon YG, Lee JH, Cheng KKY, Titchenell P, Birnbaum M, Xu A, Sancar A, Kim JB. (2016) SREBP1c-CRY1 signaling represses hepatic glucose production by promoting FOXO1 degradation during refeeding. Nat Commun.
- Lindahl T, Modrich P, Sancar A. (2016) The 2015 Nobel Prize in Chemistry The Discovery of Essential Mechanisms that Repair DNA Damage. J Assoc Genet Technol. 42(1):37-41. PMID: 27183258.
- Canturk F, Karaman M, Selby CP, Kemp MG, Kulaksiz-Erkmen G, Hu J, Li W, Lindsey-Boltz LA, Sancar A. (2016) Nucleotide excision repair by dual incisions in plants. Proc Natl Acad Sci U S A.
- Adar S, Hu J, Lieb JD, Sancar A. (2016) Genome-wide kinetics of DNA excision repair in relation to chromatin state and mutagenesis. Proc Natl Acad Sci U S A. 113(15):E2124-33.
- Kemp MG, Sancar A. (2016) ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress. J Biol Chem. (17):9330-42.
- Lindsey-Boltz LA, Kemp MG, Hu J, Sancar A. (2015) Analysis of ribonucleotide removal from DNA by human nucleotide excision repair. J Biol Chem. 290(50):29801-7.
- Choi JH, Kim SY, Kim SK, Kemp MG, Sancar A. (2015) An Integrated Approach for Analysis of the DNA Damage Response in Mammalian Cells: Nucleotide Excision Repair, DNA Damage Checkpoint, and Apoptosis. J Biol Chem. 290(48):28812:21.
- Tan C, Liu Z, Li J, Guo X, Wang L, Sancar A, Zhong D. (2015) The molecular origin of high DNA-repair efficiency by photolyase. Nat Commun. 6:7302.
- Hu J, Adar S, Selby CP, Lieb JD, Sancar A. (2015) Genome-wide analysis of human global and transcription-coupled excision repair of UV damage at single-nucleotide resolution. Genes Dev. 29(9):948-60.
- Kemp MG, Lindsey-Boltz LA, Sancar A. (2015) UV light potentiates STING (stimulator of interferon genes)-dependent innate immune signaling through deregulation of ULK1 (Unc51-like kinase 1). J Biol Chem. 290(19):12184-94.
- Lindsey-Boltz LA, Kemp MG, Capp C, Sancar A. (2015) RHINO forms a stoichiometric complex with the 9-1-1 checkpoint clamp and mediates ATR-Chk1 signaling. Cell Cycle 14(1):99-108.