Publication Date

2024

Document Type

Dissertation

Committee Members

Michael G. Kemp, Ph.D. (Advisor); Michael Leffak, Ph.D. (Committee Member); Michael P. Markey, Ph.D. (Committee Member); Yong-jie Xu, M.D., Ph.D. (Committee Member); Jeffrey B. Travers, M.D., Ph.D. (Committee Member)

Degree Name

Doctor of Philosophy (PhD)

Abstract

The circadian clock is a fundamental biological mechanism that regulates various physiological processes, including DNA repair, to synchronize with the day-night cycle. In human skin, exposure to ultraviolet (UV) light poses a significant challenge, inducing DNA damage that must be efficiently repaired to maintain genomic integrity and prevent carcinogenesis. This study delved into the complex interplay between the circadian clock, UV light exposure, DNA repair, and modulation of circadian transcriptional machinery in human skin. Initially, we examined the transcriptomic profile of the circadian clock in humans through in silico-based approaches and in vivo studies, revealing that core clock gene expression and downstream clock-controlled genes are influenced by factors such as age, sex, and UV exposure. Recognizing the potential to modify circadian clock output, we employed REV-ERB antagonist SR8278 and cryptochrome inhibitor KS15 to enhance clock function, thereby facilitating increased output of downstream processes like DNA repair. In our ex vivo model system, we found that SR8278 and KS15 were able to increase both the RNA and protein levels of ARNTL, XPA, and Wee1, as well as being able to decrease the amount of UV-induced apoptosis in some individuals. In keratinocytes in vitro, we found that treatment with SR8278 and KS15 led to significant increases in survival when exposed to UVB, but led to significant toxicity under UVA lights. Furthermore, we were able to modestly increase expression of ARNTL, XPA, Wee1 and p21 at the RNA and protein levels. However, we found that these increases did not translate to increased nucleotide excision repair capacity. Rather, we determined that the compounds are absorbing wavelengths of UV light and preventing damage formation initially. Further investigations are warranted to elucidate the precise mechanism of action of SR8278 and KS15 in modulating circadian clock function. Nevertheless, this study lays the groundwork for future research exploring the therapeutic potential of leveraging the circadian clock to address various pathophysiological skin conditions.

Page Count

193

Department or Program

Biomedical Sciences

Year Degree Awarded

2024

ORCID ID

0000-0002-6417-905x

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