Our laboratory studies how noncoding RNAs function, how cells recognize and degrade defective RNAs, and how failure to degrade these RNAs affects cell function and contributes to human disease. Most cellular RNA does not encode proteins, and truncated, misfolded and aberrant RNAs can accumulate due to mutations, transcriptional errors and processing mistakes. Some forms of environmental stress, such as exposure to oxidants and ultraviolet light, result in RNA damage, yet little is known of how damaged RNAs are recognized and handled.

One pathway that we study involves noncoding RNA-protein complexes known as Ro60 ribonucleoproteins (RNPs). These RNPs are clinically important targets of the immune system in patients suffering from two rheumatic diseases, systemic lupus erythematosus and Sjögren’s syndrome. The major protein component, the ring-shaped Ro60 autoantigen, is present in most animal cells and ~5% of bacteria. In all studied organisms, Ro60 binds noncoding RNAs called Y RNAs. By studying Ro60 in bacteria, we discovered that this protein is tethered by Y RNA to a ring-shaped nuclease, forming a double-ringed RNP machine specialized for structured RNA degradation. We showed that Ro60 contributes to survival of both mammalian cells and bacteria in the presence of stresses, such as ultraviolet light, that damage nucleic acids. We also provided evidence that bacterial Ro60 RNPs may act through molecular mimicry to trigger autoantibody formation in susceptible patients. Our current goals are to uncover additional roles for Ro60 and Y RNAs in both mammalian cells and bacteria. We are also studying ways in which this and other RNA surveillance pathways contribute to normal cell physiology and prevent diseases such as cancer.

Relevance to cancer

While much is known as to how DNA damage contributes to carcinogenesis, less is known about the effects of RNA damage. Many environmental agents that damage DNA also affect RNA integrity and alter RNA pools. For example, UV irradiation causes RNA-protein crosslinks and increases transcription of retrotransposons. Many common chemotherapeutics, such as mitomycin C and bleomycin, also damage RNA. By uncovering novel mechanisms by which cells deal with the effects of RNA damage, our work could advance understanding of the paths that lead to cancer and increase knowledge as to how chemotherapeutic agents function.