The long term goals of this project are to understand how misfolded RNAs are recognized and handled within cells and to investigate how RNA misfolding impacts cell function. Our focus is on the Ro autoantigen, an RNA-binding protein that is a major target of the immune response in patients with systemic lupus erythematosus. In the cytoplasm of many animal cells, Ro binds small RNAs called Y RNAs. Although the function of the Ro/Y RNA complex has been enigmatic, we recently demonstrated that Ro has 2 conserved cellular functions. First, Ro binds misfolded, defective small RNAs in vertebrate cell nuclei, and thus likely plays a role in small RNA quality control. Second, Ro is part of a novel pathway by which mammalian cells and at least one eubacterium survive ultraviolet irradiation. Consistent with a role in the recognition or repair of nuclear damage, Ro accumulates in nuclei following irradiation. Most surprisingly, mice lacking Ro develop an autoimmune disease that resembles systemic lupus erythematosus in patients. These findings suggest that this putative RNA quality control pathway may be important for protecting cells from environmental stress and raise the possibility that failure of RNA quality control may result in disease. Our goal is to arrive at a mechanistic understanding of Ro function and to uncover the role that Y RNAs play in these processes.
Our first aim i s to determine how Ro recognizes misfolded RNAs and to investigate whether binding by Ro targets them for degradation.
Our second aim i s to elucidate the mechanism by which Ro facilitates mammalian and bacterial cell survival following ultraviolet irradiation.
Our third aim i s to examine the role of the Y RNAs in small RNA quality control and cell survival after irradiation. As Ro is the only protein described to bind misfolded small RNAs in cells, a study of its function should provide insights into a little-studied but highly important biological process.
Showing the most recent 10 out of 25 publications
