Biochemistry and Biophysics - UNC School of Medicine
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Aziz Sancar, MD, PhD
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Interconnection between the Circadian Clock and DNA Excision Repair
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RESEARCH INTERESTS:
DNA Repair
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.
Recent News
- 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) Researchers in Aziz Sancar's group in the Dept. of Biochemistry & Biophysics at UNC-Chapel Hill have shown that disruption of the circadian clock – the internal time-keeping mechanism that keeps the body running on a 24-hour cycle – can slow the progression of cancer.
- UNC study supports the role of circadian clock in chemotherapy A new study from Aziz Sancar's group in the Dept. of Biochemistry & Biophysics at UNC-Chapel Hill suggests that chemotherapy is most effective at certain times of day because that is when a particular enzyme system – one that can reverse the actions of chemotherapeutic drugs – is at its lowest levels in the body.
RECENT PUBLICATIONS:
Ozturk N, Lee JH, Gaddameedhi S, Sancar A (2009) Loss of cryptochrome reduces cancer risk in p53 mutant mice. Proc Natl Acad Sci U S A 106:2841-2846
Kang TH, Reardon JT, Kemp M, Sancar A (2009) From the Cover: Circadian oscillation of nucleotide excision repair in mammalian brain. Proc Natl Acad Sci U S A 106:2864-2867
Choi JH, Lindsey-Boltz LA, Sancar A (2009) Cooperative activation of the ATR checkpoint kinase by TopBP1 and damaged DNA. Nucleic Acids Res, PMID:19139065
Ozturk N, Kao YT, Selby CP, Kavakli IH, Partch CL, Zhong D, Sancar A (2008) Purification and characterization of a type III photolyase from Caulobacter crescentus. Biochemistry 47:10255-10261
Kao YT, Saxena C, He TF, Guo L, Wang L, Sancar A, Zhong D (2008) Ultrafast dynamics of flavins in five redox states. J Am Chem Soc 130:13132-13139
Sancar A (2008) Structure and function of photolyase and in vivo enzymology: 50th anniversary. J Biol Chem 283:32153-32157
Wisor JP, Pasumarthi RK, Gerashchenko D, Thompson CL, Pathak S, Sancar A, Franken P, Lein ES, Kilduff TS (2008) Sleep deprivation effects on circadian clock gene expression in the cerebral cortex parallel electroencephalographic differences among mouse strains. J Neurosci 28:7193-7201
Lovejoy KS, Todd RC, Zhang S, McCormick MS, D'Aquino JA, Reardon JT, Sancar A, Giacomini KM, Lippard SJ (2008) cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects. Proc Natl Acad Sci U S A 105:8902-8907
Kao YT, Tan C, Song SH, Ozturk N, Li J, Wang L, Sancar A, Zhong D (2008) Ultrafast dynamics and anionic active states of the flavin cofactor in cryptochrome and photolyase. J Am Chem Soc 130:7695-7701
Ozturk N, Song SH, Ozgur S, Selby CP, Morrison L, Partch C, Zhong D, Sancar A (2007) Structure and function of animal cryptochromes. Cold Spring Harb Symp Quant Biol 72:119-131
Sancar A (2008) The intelligent clock and the Rube Goldberg clock. Nat Struct Mol Biol 15:23-24
Ozturk N, Song SH, Selby CP, Sancar A (2008) Animal type 1 cryptochromes. Analysis of the redox state of the flavin cofactor by site-directed mutagenesis. J Biol Chem 283:3256-3263
Kesseler KJ, Kaufmann WK, Reardon JT, Elston TC, Sancar A (2007) A mathematical model for human nucleotide excision repair: damage recognition by random order assembly and kinetic proofreading. J Theor Biol 249:361-375
Kao YT, Saxena C, Wang L, Sancar A, Zhong D (2007) Femtochemistry in enzyme catalysis: DNA photolyase. Cell Biochem Biophys 48:32-44
Choi JH, Lindsey-Boltz LA, Sancar A (2007) Reconstitution of a human ATR-mediated checkpoint response to damaged DNA. Proc Natl Acad Sci U S A 104:13301-13306
Lindsey-Boltz LA, Sancar A (2007) RNA polymerase: the most specific damage recognition protein in cellular responses to DNA damage? Proc Natl Acad Sci U S A 104:13213-13214
Song SH, Ozturk N, Denaro TR, Arat NO, Kao YT, Zhu H, Zhong D, Reppert SM, Sancar A (2007) Formation and function of flavin anion radical in cryptochrome 1 blue-light photoreceptor of monarch butterfly. J Biol Chem 282:17608-17612