Sandra L Wolin MD, PhD
Professor of Cell Biology and of Molecular Biophysics and Biochemistry; Vice Chair, Department of Cell Biology
RNA quality control; noncoding RNAs; RNA damage; autoimmune disease
We study how noncoding RNA molecules fold into intricate structures, how cells recognize and degrade misfolded, defective and damaged noncoding RNAs, and the consequences of RNA damage for cell physiology and disease. One protein under study, called Ro, is part of a novel RNA quality control pathway in both mammalian cells and bacteria. Ro is ring-shaped and binds the ends of misfolded noncoding RNAs in its central cavity, targeting these RNAs for decay. Interestingly, binding of misfolded noncoding RNAs to Ro is itself regulated by noncoding RNAs called Y RNAs. As mice lacking Ro develop an autoimmune disease that resembles systemic lupus erythematosus, Ro may be important for preventing autoimmunity. In a second effort, we are identifying other components involved in recognizing and degrading damaged RNAs in mammalian cells. Our experiments utilize a wide variety of techniques, including mouse and bacterial genetics, biochemistry, molecular biology and cell imaging.
Extensive Research Description
Our laboratory studies how cells recognize and degrade aberrant, damaged, unneeded and potentially harmful noncoding RNAs. Most cellular RNA does not code for proteins, and truncated, misfolded and aberrant noncoding RNAs can accumulate as a result of mutations, transcriptional errors and processing mistakes. Also, as retrotransposon-derived sequences make up much of mammalian genomes, the transcripts from these elements may need to be recognized and degraded. Finally, certain types of environmental stress, such as exposure to oxidants and ultraviolet light, can result in RNA damage. One pathway that we study involves a protein called the Ro 60 kDa autoantigen. Ro was discovered because it is a major target of the immune system in patients with the rheumatic diseases systemic lupus erythematosus and Sjogren’s syndrome. Ro is present in many animal cells and also in ~5% of sequenced bacterial genomes. In both mammalian cells and bacteria, Ro is important for survival after UV irradiation. Ro is shaped like a donut with a central hole and binds the ends of misfolded and defective RNAs inside its central cavity. As mice lacking Ro develop an autoimmune disease that resembles systemic lupus erythematosus, Ro may be important for preventing autoimmunity.
Interestingly, in both mammalian cells and bacteria, the function of Ro is regulated by ~100 nt long noncoding RNAs called Y RNAs. Y RNAs regulate the subcellular location of Ro and its interaction with other proteins and RNAs. We are studying the mechanisms by which Y RNAs influence Ro function. We are also characterizing other components involved in recognizing and degrading aberrant RNAs in mammalian cells and examining how they interface with the Ro pathway.