Oxidized RNA in SLE Pathology

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Project Summary SLE is a chronic autoimmune syndrome that can involve a variety of organ systems and frequently affects young individuals. It has been suggested that uncontrolled oxidative stress in the cells of SLE patients contributes to functional oxidative modifications of many proteins, lipids, and DNA, consequently triggering autoimmunity. However, the role RNA oxidation plays in the development of autoimmune diseases such as SLE is not known. Under both normal and oxidative stress conditions, RNA oxidation levels are much higher than DNA oxidation levels; however, available information on the potential effects of RNA oxidation is scarce. A major reason for the shortage of work on RNA oxidation is the misconception that normal RNA turnover should diminish effects of oxidized RNA on cell metabolism and gene expression. However, since oxidation of nucleic acids occurs in just a few minutes, and ribosomal and non-coding RNAs live in the cell for days, there is ample opportunity for oxidized RNA to have deleterious and long-standing effects. Our scientific premise is that spatial separation of RNA in the nucleus, cytoplasm, and mitochondria ensures that some RNAs will be more exposed to oxidation than others by restricting accessibility to oxidants. We propose in Aim 1 that MAVS-mediated hyperpolarization of mitochondria will stall some of the RNAs at their surface and promote their oxidation. We propose that non- coding ribosomal RNA, like 5S RNA, is greatly affected. In Aim 2, based on the fact that 5S RNA binds to its own transcription factor, we propose that RNA oxidation will lead to changes in 5S RNA gene expression, and also to a decrease in copy number variation of ribosomal genes. Data obtained in this application will provide the grounds for our upcoming R01 application investigating the novel premise that autoimmune diseases such as SLE can be associated with a disrupted ribosomal DNA copy number in the genome as a result of environmental exposure.