Aziz Sancar, MD, PhD
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SANCAR LAB NEWS:
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.
Interconnection between the Circadian Clock and DNA Excision Repair RECENT PUBLICATIONS:
Rivera AS, Ozturk N, Fahey B, Plachetzki DC, Degnan BM, Sancar A, Oakley TH. (2012) Blue-light-receptive cryptochrome is expressed in a sponge eye lacking neurons and opsin. J Exp Biol 215:1278-86 Selby CP, Sancar A. (2012) The second chromophore in Drosophila photolyase/cryptochrome family photoreceptors. Biochemistry 51:167-71 Gaddameedhi S, Selby CP, Kaufmann WK, Smart RC, Sancar A. (2011) Control of skin cancer by the circadian rhythm. Proc Natl Acad Sci U S A 108:18790-5 Liu Z, Tan C, Guo X, Kao Y-T, Li J, Wang L, Sancar A, Zhong D. (2011) Dynamics and mechanism of cyclobutane pyrimidine dimer repair by DNA photolyase. Proc Natl Acad Sci U S A 108: 14831-36 Yilmaz S, Sancar A, Kemp MG. (2011) Multiple ATR-Chk1 Pathway Proteins Preferentially Associate with Checkpoint-Inducing DNA Substrates. PLoS One 6:e22986 Lee JH, Sancar A. (2011) Regulation of apoptosis by the circadian clock through NF-kB signaling. Proc Natl Acad Sci U S A 108:12036-41 Lee JH, Sancar A. (2011) Circadian clock disruption improves the efficacy of chemotherapy through p73-mediated apoptosis. Proc Natl Acad Sci U S A 108:10668-72 Ye R, Selby CP, Ozturk N, Annayev Y, Sancar A. (2011) Biochemical Analysis of the Canonical Model for the Mammalian Circadian Clock. J Biol Chem 286:25891-902 Lindsey-Boltz LA, Sancar A. (2011) Tethering DNA Damage Checkpoint Mediator Proteins Topoisomerase IIβ-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 286: 19229-36. Kemp MG, Lindsey-Boltz LA, Sancar A. (2011) 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 286:19237-46 Kang TH, Reardon JT, Sancar A. (2010) Regulation of nucleotide excision repair activity by transcriptional and post-transcriptional control of the XPA protein. Nucleic Acids Res 39:3176-3187 Ozturk N, Selby CP, Annayev Y, Zhong D, Sancar A. (2011) Reaction mechanism of Drosophila cryptochrome. Proc Natl Acad Sci U S A 108:516-21 Gaddameedhi S, Sancar A. (2011) Melanoma and DNA damage from a distance (farstander effect). Pigment Cell Melanoma Res 24:3-4 Li J, Liu Z, Tan C, Guo X, Wang L, Sancar A, Zhong, D. (2010) Dynamics and mechanism of (6-4) photoproduct repair in damaged DNA by photolyase. Nature 466:887-90 Choi JH, Lindsey-Boltz LA, Kemp M, Mason AC, Wold MS, Sancar A. (2010) Reconstitution of RPA-covered single-stranded DNA-activated ATR-Chk1 signaling. Proc Natl Acad Sci U S A 107(31):13660-5 Gaddameedhi S, Kemp MG, Reardon JT, Shields JM, Smith-Roe SL, Kaufmann WK, Sancar A. (2010) Similar nucleotide excision repair capacity in melanocytes and melanoma cells. Cancer Res 70:4922-30 Kang TH, Lindsey-Boltz LA, Reardon JT, Sancar A. (2010) Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase. Proc Natl Acad Sci U S A 107:4890-5 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. (2010) Tipin-replication protein A interaction mediates Chk1 phosphorylation by ATR in response to genotoxic stress. J Biol Chem 285:16562-71 Sancar A, Lindsey-Boltz LA, Kang TH, Reardon JT, Lee JH, Ozturk N. (2010) Circadian clock control of the cellular response to DNA damage. FEBS Lett 584:2618-25 Liu Y, Fang Y, Shao H, Lindsey-Boltz L, Sancar A, Modrich P. (2010) Interactions of human mismatch repair proteins MutS{alpha} and MultL{alpha} with proteins of the ATR-Chk1 pathway. J Biol Chem 285:5974-82 Kemp MG, Mason AC, Carreira A, Reardon JT, Haring SJ, Borgstahl GE, Kowalczykowski SG, Sancar A, Wold MS. (2010) An alternative form of RPA (aRPA) expressed in normal human tissues supports DNA repair. J Biol Chem 285:4788-97 Kemp MG, Sancar A. (2009) DNA Distress:just ring 9-1-1. Curr Biol 19:R733-4 Lindsey-Boltz LA, Sercin O, Choi JH, Sancar A. (2009) Reconstitution of human claspin-mediated phosphorylation of Chk1 by the ATR (ataxia talangiectasia-mutated and rad3-related) checkpoint kinase. J Biol Chem 284:33107-14 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 106:2841-6 Li L, Perdigao J, Pegg AE, Lao Y, Hecht SS, Lindgren BR, Reardon JT, Sancar A, Wattenberg EV, Peterson LA. (2009) The influence of repair pathways on the cytotoxicity and mutagenicity induced by the pyridyloxobutylation pathway of tobacco-specific nitrosamines. Chem Res Toxicol 22:1464-72 Balakrishnan L, Brandt PD, Lindsey-Boltz LA, Sancar A, Bambara RA. (2009) Long patch base excision repair proceeds via coordinated stimulation of the multienzyme DNA repair complex. J Biol Chem 284:15158-72 Choi JH, Lindsey-Boltz LA, Sancar A. (2009) Cooperative activation of the ATR checkpoint kinase by TopBP1 and damaged DNA. Nucleic Acids Res 37:1501-9 Kang TH, Reardon JT, Kemp M, Sancar A. (2009) Circadian oscillation of nucleotide excision repair in mammalian brain. Proc Natl Acad Sci U S A 106:2864-7 |
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