DNA EXCISION REPAIR AND DNA DAMAGE CHECKPOINTS Nucleotide excision repair and DNA damage checkpoints are two major cellular responses to DNA damage that are essential for genomic stability. The goal of our research is to understand the molecular mechanisms of these systems and to use this information to develop cancer prevention and treatment strategies. To accomplish this goal we will perform the following experiments.
Aim 1. Nucleotide Excision Repair and Skin Cancer Development as a Function of the Circadian Clock. Our studies on the regulation of nucleotide excision repair in mammals have revealed that excision repair exhibits high amplitude oscillation with a daily periodicity in most mouse tissues. We will analyze the daily variability of excision repair of UV photoproducts in skin and determine whether this variability is associated with carcinogenicity of UV light delivered at different times of the day. The results of this study will enable us to make specific recommendations to lower the incidence of skin cancer induced by sunlight and other UV sources.
Aim 2. Biochemical Analysis of the UV-Induced DNA Damage Checkpoint. We will purify and characterize the proteins involved in ATR kinase-mediated DNA damage checkpoint response which is the primary checkpoint pathway activated by UV and UV-mimetic chemical agents. We will reconstitute this checkpoint system from highly purified components in vitro and analyze the coupling of nucleotide excision repair with the ATR checkpoint signaling pathway. Understanding this DNA damage signaling pathway should facilitate the design of novel chemotherapeutic approaches to treat cancer.

Public Health Relevance

We propose to carry out experiments on two major cellular responses to UV- and UV-mimetic drug- induced DNA damage: Translational research on nucleotide excision repair in mice and mechanistic research on ATR-mediated DNA damage checkpoints. We will use biochemical, cell biological, genetic, and animal model systems in our research and provide mechanistic and animal model data for cancer prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM032833-31
Application #
8640182
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Janes, Daniel E
Project Start
1983-12-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
31
Fiscal Year
2014
Total Cost
$612,652
Indirect Cost
$198,698
Name
University of North Carolina Chapel Hill
Department
Biochemistry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kemp, Michael G; Sancar, Aziz (2016) ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress. J Biol Chem 291:9330-42
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
Song, Jimyeong; Kemp, Michael G; Choi, Jun-Hyuk (2016) Detection of the Excised, Damage-containing Oligonucleotide Products of Nucleotide Excision Repair in Human Cells. Photochem Photobiol :
Canturk, Fazile; Karaman, Muhammet; Selby, Christopher P et al. (2016) Nucleotide excision repair by dual incisions in plants. Proc Natl Acad Sci U S A 113:4706-10
Kemp, Michael G; Hu, Jinchuan (2016) PostExcision Events in Human Nucleotide Excision Repair. Photochem Photobiol :
Kemp, Michael G; Lindsey-Boltz, Laura A; Sancar, Aziz (2015) UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1). J Biol Chem 290:12184-94
Lindsey-Boltz, Laura A; Kemp, Michael G; Capp, Christopher et al. (2015) RHINO forms a stoichiometric complex with the 9-1-1 checkpoint clamp and mediates ATR-Chk1 signaling. Cell Cycle 14:99-108
Sancar, Aziz; Lindsey-Boltz, Laura A; Gaddameedhi, Shobhan et al. (2015) Circadian clock, cancer, and chemotherapy. Biochemistry 54:110-23
Choi, Jun-Hyuk; Kim, So-Young; Kim, Sook-Kyung et al. (2015) An Integrated Approach for Analysis of the DNA Damage Response in Mammalian Cells: NUCLEOTIDE EXCISION REPAIR, DNA DAMAGE CHECKPOINT, AND APOPTOSIS. J Biol Chem 290:28812-21
Lindsey-Boltz, Laura A; Kemp, Michael G; Hu, Jinchuan et al. (2015) Analysis of Ribonucleotide Removal from DNA by Human Nucleotide Excision Repair. J Biol Chem 290:29801-7

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