Mechanisms of reversible DUB oxidation in genome stability pathways - Revision

PROJECT SUMMARY/Abstract: The current pandemic of COVID-19 (Coronavirus Disease-2019), a respiratory disease that hasled to over 5 million confirmed cases and over 350,000 fatalities in over 100 countries since its emergence in late 2019, is caused by a novel virus strain, SARS-CoV-2, an enveloped, positive-sense, single-stranded RNA beta-coronavirus of the family Coronaviridae. My lab has a long-standing interest in understanding how cellular DUBs are regulated by environmentally-produced small molecules, including ROS, toxic heavy metals, chemical pollutants and carcinogens. Similar to human DUBs, viral DUBs, such as the coronavirus Plpro, are proteases that cleave ubiquitinor ubiquitin-like proteins from pro-proteins or from conjugates on target proteins. In doing so, viral DUBs hijack the balance of ubiquitination dynamics in infected cells, potentially disrupting numerous cellular functions, including cell cycle regulation, proteasomal and lysosomal protein degradation, gene expression, kinase activation, DNA repair and ultimately favoring microbial pathogenesis. How viral DUBs are particularly susceptible to environmental exposures, such as ROS and chemical pollutants, have not been adequately explored, especially as novel modulators of human pathogenesis. As it pertains to the rapid global spread of SARS-CoV-2 and the prevalence of COVID-19 disease in the U.S. population and worldwide, we will be focusing our research goals on understanding 1) how the SARS-CoV-2 Plpro protease activity (cleavage of pro-proteins, ubiquitin-, and ISG15-conjugated proteins) can be regulated by environmentally-generated small molecules, and 2) identifying COVID-19 disease-relevant cellular targets of thePlpro upon viral infection in human lung epithelial cells.