Despite significant advances in understanding the biochemical basis of nucleotide excision repair (NER), there is no cure for individuals with Xeroderma pigmentosum, Cockayne Syndrome, Fanconi Anemia, and other DNA repair defects. Current therapy is focused on relieving symptoms and improving quality of life. The ubiquitin/proteasome system (UPS) of interacellular protein degradation has been extensively studied, and is implicated in cell cycle control, stress response, signal transduction, and DNA repair. We determined that the NER protein Rad4 is highly unstable, and is rapidly degraded by the proteasome. Remarkably, a number of additional DNA repair proteins have protein degradation functions, including Rad6, Rad7, Rad16 and FANCL. My laboratory has, for the past 15 years, investigated the role of protein degradation in DNA repair. We determined that Rad4 is stabilized when it forms a complex with the DNA repair factor, Rad23. Rad23 can also bind the proteasome and deliver ubiquitinated substrates. We recently discovered that the localization of proteasomes at the nuclear periphery is required for DNA repair. The studies proposed here will use genetic, biochemical and cell biological approaches to investigate the role of the UPS in nucleotide excision repair. We will characterize the proteins that traffic proteasomes, and determine how nuclear substrates, including Rad4, are targeted to the proteasome. These mechanistic studies are expected to have a broad impact, as they will show that proteasome trafficking represents a previously unknown regulatory process in intracellular protein degradation.

Public Health Relevance

The primary objective of the proposed studies is to investigate the role of protein degradation in DNA repair. Xeroderma pigmentosum and Cockayne Syndrome are well studied DNA repair defects for which there is no treatment or cure. Our studies could pave the way towards identification of candidate proteins and biochemical functions that can be targeted by therapeutic agents.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Radiation Therapeutics and Biology Study Section (RTB)
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Okano, Paul
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University of Medicine & Dentistry of NJ
Schools of Medicine
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