The long-term objectives of this project are to delineate the molecular mechanisms of interpathway interactions between nucleotide excision repair (NER) and DNA damage checkpoints. NER and the damage checkpoints are two major components in cellular responses to DNA damage due to formation of bulky lesions induced by UV irradiation and various environmental genotoxic chemicals and carcinogens. Defects in these pathways have been directly correlated to human cancer prone deceases such as xeroderma pigmentosum (XP) and Ataxia-Telangiectasia (AT). Although great efforts have been made in understanding the overall mechanism of cellular DNA damage responses, the molecular details about the relationship between the two pathways remain elusive due to the fact that the two systems have been largely studied separately. To gain a more systematic and precise view of cellular responses to DNA damage, experiments and strategies are developed to address the following questions: How the DNA damage checkpoints and DNA repair are coordinated in cells upon DNA damage? What are the protein factors involved in the interactions? And what is the molecular basis of the interactions? Using a combined biochemical, molecular biology and structural approach, this project aims (1) to define the role XPA in ATR regulation of NER and the cell-cycle dependency of the regulation for testing the hypothesis that XPA is the main target in NER for regulation of NER functions by ATR checkpoint;(2) to determine the effects of ATR-XPA protein-protein interaction on DNA damage responses to UV and to test the underlying hypothesis that the interaction is a determinant for nuclear accumulation of XPA for NER regulated by ATR upon UV irradiation;(3) to examine the dependence of nuclear-translocation of XPA on ATR checkpoint signaling. We will test the hypothesis that ATR checkpoint signaling is required for the DNA damage-induced cytoplasm-to-nuclear trafficking of XPA;and (4) to assess the role of ATR- regulated XPA phosphorylation in DNA damage responses and the effects of XPA phosphorylation on nucleotide excision repair.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA086927-09
Application #
8115776
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2000-07-01
Project End
2013-10-31
Budget Start
2011-08-01
Budget End
2013-10-31
Support Year
9
Fiscal Year
2011
Total Cost
$227,830
Indirect Cost
Name
East Tennessee State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
051125037
City
Johnson City
State
TN
Country
United States
Zip Code
37614
Wu, Xi; Dong, Zizheng; Wang, Chao J et al. (2016) FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-?B and SP1. Proc Natl Acad Sci U S A 113:E6965-E6973
Hilton, Benjamin; Gopal, Sathyaraj; Xu, Lifang et al. (2016) Dissociation Dynamics of XPC-RAD23B from Damaged DNA Is a Determining Factor of NER Efficiency. PLoS One 11:e0157784
Wang, Yan; Musich, Phillip R; Cui, Kui et al. (2015) Neurotoxin-induced DNA damage is persistent in SH-SY5Y cells and LC neurons. Neurotox Res 27:368-83
Hilton, Benjamin A; Li, Zhengke; Musich, Phillip R et al. (2015) ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1. Mol Cell 60:35-46
Hilton, Benjamin; Shkriabai, Nick; Musich, Phillip R et al. (2014) A new structural insight into XPA-DNA interactions. Biosci Rep 34:e00162
Wang, Yan; Musich, Phillip R; Serrano, Moises A et al. (2014) Effects of DSP4 on the noradrenergic phenotypes and its potential molecular mechanisms in SH-SY5Y cells. Neurotox Res 25:193-207
Serrano, M A; Li, Z; Dangeti, M et al. (2013) DNA-PK, ATM and ATR collaboratively regulate p53-RPA interaction to facilitate homologous recombination DNA repair. Oncogene 32:2452-62
Jain, Vipin; Hilton, Benjamin; Lin, Bin et al. (2013) Structural and thermodynamic insight into Escherichia coli UvrABC-mediated incision of cluster diacetylaminofluorene adducts on the NarI sequence. Chem Res Toxicol 26:1251-62
Jain, Vipin; Hilton, Benjamin; Lin, Bin et al. (2013) Unusual sequence effects on nucleotide excision repair of arylamine lesions: DNA bending/distortion as a primary recognition factor. Nucleic Acids Res 41:869-80
Li, Zhengke; Musich, Phillip R; Cartwright, Brian M et al. (2013) UV-induced nuclear import of XPA is mediated by importin-?4 in an ATR-dependent manner. PLoS One 8:e68297

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