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)
- 1971 – 1973 NATO Fellowship
- 1977 PhD, University of Texas at Dallas
- 1984 – 1989 NSF Presidential Young Investigator Award
- 1990 American Society for Photobiology Award
- 1995 Turkish Scientific Research Council Basic Science Award
- 1995 – 2004 NIH MERIT Award
- 1997 – Present Sarah Graham Kenan Professor
- 2001 North Carolina Distinguished Chemist Award, ACS
- 2002 Miller Visiting Professor-UC Berkeley
- 2004 American Academy of Arts and Sciences
- 2005 National Academy of Sciences, USA
- 2006 Turkish Academy of Sciences
- 2007 Turkish Koç Award
- 2009 Distinguished Alumni Award (Univ. of Texas at Dallas)
- 2014 Distinguished Visiting Professor – Academia Sinica
- 2015 Nobel Prize in Chemistry
- 2016 TWESCO International Turkish Academy – Gold Medal at UN
- 2016 ASBMB Bert and Natalie Vallee Award
- 2016 O. Max Gardner Award (highest honor by University of North Carolina 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
- 2018 Lifetime Achievement Award (Univ. of Texas at Dallas)
- 2019 Hyman L. Battle Distinguished Cancer Research Award
- 2006-2019 Honorary Doctorates from Turkey, Azerbaijan, Kazakhstan, Kyrgyzstan, Uzbekistan, Peru
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.
- Putker M, Wong CSD, Seinkmane E, Rzechorzek NM, Zeng A, Hoyle NP, Chesham JE, Edwards MD, Feeney KA, Fischer R, Peschel N, Chen K-F, Oever MV, Edgar RS, Selby CP, Sancar A, O’Neill JS (2021) CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping. EMBO Journal e106745
- Cao X, Yang Y, Selby CP, Liu Z, Sancar A (2021) Molecular mechanism of the repressive phase of the mammalian circadian clock. Proceedings of the National Academy of Sciences of the United States of America 118(2), e2021174118
- Sancar A (2021) My 100th JBC paper. The Journal of biological chemistry 296 100061
- Sancar A, Van Gelder RN (2021) Clocks, cancer, and chronochemotherapy. Science (New York, N.Y.) 371(6524)
- Chiou YY, Li TY, Yang Y, Sancar A (2020) A Sextuple Knockout Cell Line System to Study the Differential Roles of CRY, PER, and NR1D in the Transcription-Translation Feedback Loop of the Circadian Clock. Frontiers in neuroscience 14 616802
- Selby CP, Lindsey-Boltz LA, Yang Y, Sancar A (2020) Mycobacteria excise DNA damage in 12- or 13-nucleotide-long oligomers by prokaryotic-type dual incisions and performs transcription-coupled repair. The Journal of biological chemistry 295(50), 17374-17380
- Circadian regulation of c-MYC in mice. Liu Z, Selby CP, Yang Y, Lindsey-Boltz LA, Cao X, Eynullazada K, Sancar A. Proc Natl Acad Sci U S A. 2020 Aug 19:202011225. doi: 10.1073/pnas.2011225117. PMID: 32817420
- Genome-wide circadian rhythm detection methods: systematic evaluations and practical guidelines. Mei W, Jiang Z, Chen Y, Chen L, Sancar A, Jiang Y. Brief Bioinform. 2020 Jul 16:bbaa135. doi: 10.1093/bib/bbaa135. PMID: 32672832
- CRY1-CBS binding regulates circadian clock function and metabolism. Cal-Kayitmazbatir S, Kulkoyluoglu-Cotul E, Growe J, Selby CP, Rhoades SD, Malik D, Oner H, Asimgil H, Francey LJ, Sancar A, Kruger WD, Hogenesch JB, Weljie A, Anafi RC, Kavakli IH. FEBS J. 2020 May 8. doi: 10.1111/febs.15360. PMID: 32383312
- The circadian clock shapes the Arabidopsis transcriptome by regulating alternative splicing and alternative polyadenylation. Yang Y, Li Y, Sancar A, Oztas O. J Biol Chem. 2020 May 29;295(22):7608-7619. doi: 10.1074/jbc.RA120.013513. Epub 2020 Apr 17. PMID: 32303634
- Genome-wide single-nucleotide resolution of oxaliplatin-DNA adduct repair in drug-sensitive and -resistant colorectal cancer cell lines. Vaughn CM, Selby CP, Yang Y, Hsu DS, Sancar A. J Biol Chem. 2020 May 29;295(22):7584-7594. doi: 10.1074/jbc.RA120.013347. Epub 2020 Apr 16. PMID: 32299912
- Methodologies for detecting environmentally induced DNA damage and repair. Li W, Sancar A. Environ Mol Mutagen. 2020 Aug;61(7):664-679. doi: 10.1002/em.22365. Epub 2020 Feb 29. PMID: 32083352 Review.
- Drosophila, which lacks canonical transcription-coupled repair proteins, performs transcription-coupled repair. Deger N, Yang Y, Lindsey-Boltz LA, Sancar A, Selby CP.
J Biol Chem. 2019 Nov 29;294(48):18092-18098. doi: 10.1074/jbc.AC119.011448. Epub 2019 Oct 17. PMID: 31624146
- DCAF7 is required for maintaining the cellular levels of ERCC1-XPF and nucleotide excision repair. Kawara H, Akahori R, Wakasugi M, Sancar A, Matsunaga T. Biochem Biophys Res Commun. 2019 Oct 29;519(1):204-210. doi: 10.1016/j.bbrc.2019.08.147. Epub 2019 Sep 4. PMID: 31493872
- 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.