Pathology Presents: Genetic, Molecular, and Chemical Approaches to Dissect UV-Induced DNA Damage Responses

Speaker

Masaoki Kawasumi, MD, PhD
Acting Assistant Professor
Division of Dermatology
University of Washington

Faculty Sponsor

Paul Nghiem, MD, PhD

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Description

Why Attend?

Genetic, Molecular, and Chemical Approaches to Dissect UV-Induced DNA Damage Responses and Inhibit Skin Cancers

Ultraviolet (UV) from one-hour of sunlight generates 100,000 DNA lesions per cell that are potentially mutagenic, leading to the most prevalent cancers in humans. Understanding how cells respond to UV-induced DNA lesions could be helpful to selectively kill DNA-damaged cells and prevent UV-associated skin cancers. Strikingly, multiple human epidemiological and mouse studies have demonstrated that caffeine suppresses UV-induced skin cancer development. We found that genetic inhibition of ATR (a caffeine-sensitive kinase important in surviving DNA damage) suppresses UV carcinogenesis. These findings support ATR inhibition as the relevant mechanism for the cancer-preventive effect of caffeinated beverage intake. To better understand UV-induced DNA damage responses, we recently dissected the differential roles of two major types of UV-induced DNA lesions (cyclobutane pyrimidine dimers and 6-4 photoproducts) in ATR pathway activation and DNA replication blockage. This molecular study suggests that caffeine or ATR inhibition may suppress translesion synthesis, thereby reducing mutation burden. To discover novel druggable targets in the ATR pathway, we performed a phenotype-based screen of 9,195 small-molecule compounds and identified four compounds that inhibit the ATR pathway but are mechanistically distinct from typical ATR kinase catalytic inhibitors. This chemical genetic approach highlights the complexity of the ATR pathway, and these ATR pathway inhibitors can be used to further elucidate novel druggable mechanisms in this signaling pathway. Collectively, these three different approaches to dissect DNA damage responses could lead to more effective means to combat UV carcinogenesis.