Global genome nucleotide excision repair (GG-NER) is the major DNA repair system for removing bulky DNA damage induced by environmental carcinogens including solar ultraviolet B (UVB) radiation and air pollutants. Functional GG-NER is essential for maintaining genomic integrity and preventing tumorigenesis in the skin, lung and brain. Promoting GG-NER may have high potential for cancer prevention and therapy. Although the biochemical reactions in damage recognition and repair have been identified, the molecular mechanisms in regulating GG-NER capacity remain largely unknown. Recently, we discovered a novel role for autophagy in promoting GG-NER. As a catabolic process of degrading damaged or unnecessary proteins or organelles, autophagy is a pleiotropic cell survival mechanism with both pro- and anti-tumor effects. The goal of this proposal is to determine the mechanism by which autophagy regulates GG-NER and its impact on UVB-induced skin tumorigenesis and tumor progression. Our recently published work and preliminary data imply that autophagy's enhancement of GG-NER is associated with tumor suppression, and deserves further investigation. Thus we hypothesize that autophagy enhances GG-NER and thus suppresses UVB-induced skin tumorigenesis and tumor progression. To test our hypothesis, we propose the following specific aims.
In Aim 1 we will determine the molecular mechanism by which UVB-induced autophagy regulates Twist1.
In Aim 2 we will determine the mechanism by which Twist1 suppresses XPC transcription.
In Aim 3 we will determine the consequences of autophagy inhibition in UVB-induced skin tumorigenesis and tumor progression in mice. Our team is well positioned to carry out the proposed studies, since we have gained extensive expertise through our recent relevant work and pilot studies, and have created critical reagents and mice for the proposed experiments. Our proposed research may vastly expand our knowledge of GG-NER regulation and tumor suppression by autophagy, and provide new molecular insights for developing potent peptide mimics to promote GG-NER for skin cancer prevention and intervention. Caners arise in the skin more than in any other organ site, most likely due to environmental damage. In addition, our work here in GG-NER and autophagy is not only significant in skin cancer, but is also applicable to other tumor types as well.

Public Health Relevance

Environmental carcinogens including solar ultraviolet B (UVB) radiation and air pollutants cause cancer largely by inducing DNA damage. These DNA damage products across the whole genome are removed by global genome nucleotide excision repair (GG-NER), the most versatile DNA repair system. The proposed project will determine the mechanism of GG-NER regulation by autophagy, and its impact on UVB-induced skin tumorigenesis and tumor progression, and provide new molecular insights for developing effective GG-NER modulators for cancer prevention and therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES024373-04
Application #
9418608
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Humble, Michael C
Project Start
2015-05-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Qiang, Lei; Sample, Ashley; Shea, Christopher R et al. (2017) Autophagy gene ATG7 regulates ultraviolet radiation-induced inflammation and skin tumorigenesis. Autophagy 13:2086-2103
Qiang, Lei; Sample, Ashley; Liu, Han et al. (2017) Epidermal SIRT1 regulates inflammation, cell migration, and wound healing. Sci Rep 7:14110
Sample, Ashley; Zhao, Baozhong; Wu, Chunli et al. (2017) The Autophagy Receptor Adaptor p62 is Up-regulated by UVA Radiation in Melanocytes and in Melanoma Cells. Photochem Photobiol :
Shah, Palak; Trinh, Elaine; Qiang, Lei et al. (2017) Arsenic Induces p62 Expression to Form a Positive Feedback Loop with Nrf2 in Human Epidermal Keratinocytes: Implications for Preventing Arsenic-Induced Skin Cancer. Molecules 22:
Zhao, Baozhong; Shah, Palak; Qiang, Lei et al. (2017) Distinct Role of Sesn2 in Response to UVB-Induced DNA Damage and UVA-Induced Oxidative Stress in Melanocytes. Photochem Photobiol 93:375-381
Yang, Seungwon; Qiang, Lei; Sample, Ashley et al. (2017) NF-?B Signaling Activation Induced by Chloroquine Requires Autophagosome, p62 Protein, and c-Jun N-terminal Kinase (JNK) Signaling and Promotes Tumor Cell Resistance. J Biol Chem 292:3379-3388
Sample, Ashley; Zhao, Baozhong; Qiang, Lei et al. (2017) Adaptor protein p62 promotes skin tumor growth and metastasis and is induced by UVA radiation. J Biol Chem 292:14786-14795
Sample, Ashley; He, Yu-Ying (2017) Autophagy in UV Damage Response. Photochem Photobiol 93:943-955
Zhao, Baozhong; Qiang, Lei; Joseph, Joy et al. (2016) Mitochondrial dysfunction activates the AMPK signaling and autophagy to promote cell survival. Genes Dis 3:82-87
Qiang, L; Shah, P; Barcellos-Hoff, M H et al. (2016) TGF-? signaling links E-cadherin loss to suppression of nucleotide excision repair. Oncogene 35:3293-302

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