ROLE OF CRYPTOCHROME IN DNA DAMAGE RESPONSES AND THE CIRCADIAN CLOCK : Cryptochrome is a photosensory flavoprotein and a core component of the molecular clock which regulates the circadian rhythms of many physiological functions. We have recently discovered that cryptochrome and the molecular clock regulate cellular responses to genotoxic stress including DNA repair, apoptosis, and DNA damage checkpoints. The goal of this research project is to understand how the circadian clock controls cellular responses to DNA damage and how cryptochrome carries out its light-dependent and light-independent functions in the animal circadian clock. To accomplish these two goals we will perform the following experiments.
Aim 1 : Circadian Regulation of Cellular Responses to DNA damage. a) Regulation of Nucleotide Excision Repair. We recently discovered that excision repair exhibits high amplitude circadian oscillation in mice and humans. We will use genetic and biochemical approaches to understand the regulatory mechanism and establish a rational basis for chronochemotherapy. b) Regulation of Apoptosis by Cryptochrome. We have found that inactivation of Cryptochrome in p53 null mice derepresses an apoptotic pathway. We will solve the mechanism of apoptosis reactivation and investigate its potential use in cancer chemotherapy. c) Regulation of DNA Checkpoints. We have found that the UV damage-initiated checkpoint response is regulated by the clock. We will investigate the molecular basis of this connection.
Aim2 : Mechanism of the Action of Cryptochrome in the Circadian Clock. a) Repressor Function. We will purify mammalian cryptochrome and other clock proteins and determine the mechanism by which cryptochrome inhibits the Clock-BMal1 activator in an in vitro system. b) Photosensory Function. We will conduct photochemical/photophysical experiments to elucidate the photosensory function of cryptochrome.

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We propose to characterize the role of cryptochrome in cellular responses to genotoxic stress, including repair, apoptosis, and cell cycle checkpoints, and to characterize how cryptochrome carries out its light-dependent and light-independent functions in the animal circadian clock. We will use genetic and biochemical approaches to understand these regulatory mechanisms and establish a rational basis for chronochemotherapy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics A Study Section (MGA)
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Barski, Oleg
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Krishnaiah, Saikumari Y; Wu, Gang; Altman, Brian J et al. (2017) Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism. Cell Metab 25:961-974.e4
Chiou, Yi-Ying; Yang, Yanyan; Rashid, Naim et al. (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 113:E6072-E6079
Jang, Hagoon; Lee, Gha Young; Selby, Christopher P et al. (2016) SREBP1c-CRY1 signalling represses hepatic glucose production by promoting FOXO1 degradation during refeeding. Nat Commun 7:12180
Adar, Sheera; Hu, Jinchuan; Lieb, Jason D et al. (2016) Genome-wide kinetics of DNA excision repair in relation to chromatin state and mutagenesis. Proc Natl Acad Sci U S A 113:E2124-33
Tan, Chuang; Liu, Zheyun; Li, Jiang et al. (2015) The molecular origin of high DNA-repair efficiency by photolyase. Nat Commun 6:7302
Hu, Jinchuan; Adar, Sheera; Selby, Christopher P et al. (2015) Genome-wide analysis of human global and transcription-coupled excision repair of UV damage at single-nucleotide resolution. Genes Dev 29:948-60
Sancar, Aziz; Lindsey-Boltz, Laura A; Gaddameedhi, Shobhan et al. (2015) Circadian clock, cancer, and chemotherapy. Biochemistry 54:110-23
Ozturk, Nuri; Selby, Christopher P; Zhong, Dongping et al. (2014) Mechanism of photosignaling by Drosophila cryptochrome: role of the redox status of the flavin chromophore. J Biol Chem 289:4634-42
Ye, Rui; Selby, Cristopher P; Chiou, Yi-Ying et al. (2014) Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock. Genes Dev 28:1989-98
Annayev, Yunus; Adar, Sheera; Chiou, Yi-Ying et al. (2014) Gene model 129 (Gm129) encodes a novel transcriptional repressor that modulates circadian gene expression. J Biol Chem 289:5013-24

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