We work on three inter-related subjects: mammalian DNA excision repair, DNA damage checkpoints, and the circadian clock. We have made a number of recent discoveries in all three areas that lead to deeper understanding of the interconnections between these three systems and are directly relevant to human health and disease treatment. We developed the XR-seq (excision Repair-sequencing) method to generate an excision repair map of the entire human genome at single nucleotide resolution; we have reconstituted an in vitro system that links nucleotide excision repair to the DNA damage checkpoint; and we have discovered regulation of excision repair by the circadian clock and developed novel approaches to understand the molecular mechanism of the mammalian circadian clock. We will apply these new conceptual and technical advances for the following objectives: (1) understand factors that affect excision repair of DNA damage by carcinogenic and by anticancer agents, (2) improve the in vitro system of excision repair-checkpoint coupling for potential use in anticancer drug screening and validation, and (3) characterize the molecular mechanism of the mammalian circadian clock and develop strategies of cancer prevention and cancer treatment based on clock control of human DNA excision repair activity. This approach is innovative because it combines biochemistry/biophysics, cell biology, genetics and animal physiology to understand the mechanistic basis and connections between mammalian DNA excision repair, DNA damage checkpoints, and of the circadian clock. The proposed research is significant because of its relevance to cancer prevention and treatment.

Public Health Relevance

The goal of this research is to understand the molecular mechanisms of excision repair, DNA damage checkpoints, and the circadian clock and to apply this information for cancer prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM118102-02
Application #
9251831
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Barski, Oleg
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
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
Wang, Xuefeng; Jing, Chengyu; Selby, Christopher P et al. (2018) Comparative properties and functions of type 2 and type 4 pigeon cryptochromes. Cell Mol Life Sci 75:4629-4641
Yang, Yanyan; Adebali, Ogun; Wu, Gang et al. (2018) Cisplatin-DNA adduct repair of transcribed genes is controlled by two circadian programs in mouse tissues. Proc Natl Acad Sci U S A 115:E4777-E4785
Li, Wentao; Adebali, Ogun; Yang, Yanyan et al. (2018) Single-nucleotide resolution dynamic repair maps of UV damage in Saccharomyces cerevisiae genome. Proc Natl Acad Sci U S A 115:E3408-E3415
Chiou, Yi-Ying; Hu, Jinchuan; Sancar, Aziz et al. (2018) RNA polymerase II is released from the DNA template during transcription-coupled repair in mammalian cells. J Biol Chem 293:2476-2486
Oztas, Onur; Selby, Christopher P; Sancar, Aziz et al. (2018) Genome-wide excision repair in Arabidopsis is coupled to transcription and reflects circadian gene expression patterns. Nat Commun 9:1503
Hu, Jinchuan; Selby, Christopher P; Adar, Sheera et al. (2017) Molecular mechanisms and genomic maps of DNA excision repair in Escherichia coli and humans. J Biol Chem 292:15588-15597
Sancar, Aziz (2017) Claud S. Rupert (1919-2017): The Father of DNA Repair. Photochem Photobiol 93:1133-1134
Adebali, Ogun; Chiou, Yi-Ying; Hu, Jinchuan et al. (2017) Genome-wide transcription-coupled repair in Escherichia coli is mediated by the Mfd translocase. Proc Natl Acad Sci U S A 114:E2116-E2125
Lindsey-Boltz, Laura A (2017) Bringing It All Together: Coupling Excision Repair to the DNA Damage Checkpoint. Photochem Photobiol 93:238-244
Selby, Christopher P (2017) Mfd Protein and Transcription-Repair Coupling in Escherichia coli. Photochem Photobiol 93:280-295

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