Aziz Sancar, PhD

• Publication List

RESEARCH INTERESTS:

DNA Repair; DNA Damage Checkpoints; Regulation Of The Circadian Clock In Mammalian Organisms

We are conducting research in three interrelated fields, DNA repair, DNA damage checkpoints, and regulation of the biological (circadian) clock by light.

DNA Repair

We are studying the molecular mechanism of nucleotide excision repair in humans. This is a general repair system that repairs all DNA base lesions including the two main carcinogenic lesions, the cyclobutane pyrimidine dimer and the benzo[a]pyrene-guanine adduct induced in DNA by the two main environmental carcinogens, sunlight and cigarette smoke, respectively. Excision repair also removes the DNA lesions caused by chemotherapeutic agents such as cisplatin. Excision repair is carried out by the sequential and partly overlapping action of 6 repair factors: XPA, RPA, XPC, TFIIH, XPG, and XPF. Our lab was the first to purify these 6 factors, reconstitute the excision nuclease in a defined system, and demonstrate that it removes the damage from DNA by cutting the damaged strand on both sides of the lesion and releasing the damaged base in a 24-32 nucleotide-long oligomer. The resulting gap is filled in by DNA polymerases and ligated. 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 while keeping the gratuitous and potentially mutagenic attack on undamaged DNA to a minimum. In addition, we are characterizing the role of the excision nuclease in aging and the repair of endogenous DNA damage and as a potential target for developing new approaches to anticancer chemotherapy.

DNA Damage Checkpoints

DNA damage checkpoints are biochemical pathways that transiently block cell cycle progression while the DNA contains damage. 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. 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, biochemical methods, and neurobiological methods including mice activity profiles. In addition, we are investigating the connection between the circadian cycle and the cell cycle checkpoints and how disruption of the circadian cycle might affect the susceptibility of mice and humans to cancers.

RECENT PUBLICATIONS:

Sancar A. The intelligent clock and the Rube Goldberg clock. Nat Struct Mol Biol. 2008 Jan;15(1):23-4

Ozturk N, Song SH, Selby CP, Sancar A. Animal type1 cryptochromes: Analysis of the redox state of the flavin cofactor by site-directed mutagenesis. J Biol Chem. 2007 Dec 5

Kesseler KJ, Kaufmann WK, Reardon JT, Elston TC, Sancar A. A mathematical model for human nucleotide excision repair: damage recognition by random order assembly and kinetic proofreading. J Theor Biol. 2007 Nov 21;249(2):361-75. Epub 2007

Kao YT, Saxena C, Wang L, Sancar A, Zhong D. Femtochemistry in enzyme catalysis: DNA photolyase. Cell Biochem Biophys. 2007;48(1):32-44

Choi JH, Lindsey-Boltz LA, Sancar A. Reconstitution of a human ATR-mediated checkpoint response to damaged DNA. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13301-6. Epub 2007

Lindsey-Boltz LA, Sancar A. RNA polymerase: the most specific damage recognition protein in cellular responses to DNA damage? Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13213-4. Epub 2007

Song SH, Oztürk N, Denaro TR, Arat NO, Kao YT, Zhu H, Zhong D, Reppert SM, Sancar A. Formation and function of flavin anion radical in cryptochrome 1 blue-light photoreceptor of monarch butterfly. J Biol Chem. 2007 Jun 15;282(24):17608-12. Epub 2007

Sokolova O, Cecala C, Gopal A, Cortazar F, McDowell-Buchanan C, Sancar A, Gindt YM, Schelvis JP. Resonance Raman spectroscopic investigation of the light-harvesting chromophore in escherichia coli photolyase and Vibrio cholerae cryptochrome-1.

Biochemistry. 2007 Mar 27;46(12):3673-81. Epub 2007

Unsal-Kaçmaz K, Chastain PD, Qu PP, Minoo P, Cordeiro-Stone M, Sancar A, Kaufmann WK. The human Tim/Tipin complex coordinates an Intra-S checkpoint response to UV that slows replication fork displacement. Mol Cell Biol. 2007 Apr;27(8):3131-42. Epub 2007

Heffernan TP, Unsal-Kaçmaz K, Heinloth AN, Simpson DA, Paules RS, Sancar A, Cordeiro-Stone M, Kaufmann WK. Cdc7-Dbf4 and the human S checkpoint response to UVC. J Biol Chem. 2007 Mar 30;282(13):9458-68. Epub 2007

Roberts RB, Thompson CL, Lee D, Mankinen RW, Sancar A, Threadgill DW. Wildtype epidermal growth factor receptor (Egfr) is not required for daily locomotor or masking behavior in mice. J Circadian Rhythms. 2006 Nov 16;4:15

Ozgür S, Sancar A. Analysis of autophosphorylating kinase activities of Arabidopsis and human cryptochromes. Biochemistry. 2006 Nov 7;45(44):13369-74

Selby CP, Sancar A. A cryptochrome/photolyase class of enzymes with single-stranded DNA-specific photolyase activity. Proc Natl Acad Sci U S A. 2006 Nov 1;103(47) :17696-700. Epub 2006