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SANDRA WOLIN

Our laboratory studies how cells recognize and handle damaged, unneeded and potentially harmful noncoding RNAs and how the failure to degrade these RNAs impacts mammalian cell function and human disease. Our experiments utilize a variety of techniques, including biochemistry, cell biology, mouse and bacterial genetics, cell imaging and structural biology. Interestingly, our work has revealed unexpected connections between noncoding RNA surveillance pathways, cell survival after environmental stress, and autoimmune disease.

A novel RNA surveillance pathway in mammalian cells and bacteria

One pathway that we study involves the Ro protein, which binds noncoding RNAs that are destined for decay. Ro is present in many animal cells and in ~5% of sequenced bacterial genomes. In collaboration with Karin Reinisch, we showed that Ro is shaped like a donut with a central hole. The 3' ends of RNA substrates insert through the hole, while helical portions bind on the outer surface. In bacteria, we have shown that binding by Ro to defective RNAs assists their degradation by exonucleases. Experiments are in progress to determine if Ro functions similarly in mammalian cells. As both mammalian cells and bacteria lacking Ro are sensitive to ultraviolet irradiation, another goal is to identify the targets of Ro after irradiation. Amazingly, mice lacking Ro develop an autoimmune disease that resembles systemic lupus erythematosus in patients. This result raises the possibility that lack of Ro function contributes to autoimmune disease in humans.

Noncoding Y RNAs regulate Ro function
In both mammalian cells and bacteria, Ro associates with ~100 nt noncoding RNAs called Y RNAs. By studying these RNAs, we discovered that Y RNAs modulate the binding of RNA substrates and protein partners to Ro. Additionally, in mammalian cells, Y RNAs block a nuclear accumulation signal on Ro, retaining it in the cytoplasm. Following either UV irradiation or oxidative stress, this signal becomes accessible, allowing Ro to accumulate in nuclei. We are investigating the molecular mechanisms by which Y RNAs influence the subcellular location of Ro and its interactions with other components.

Determining how other noncoding RNA surveillance pathways interface with the Ro/Y RNA pathway
An important question raised by our work is how the Ro/Y RNA pathway interfaces with other RNA surveillance pathways, such as the pathway mediated by the exonuclease complex known as the exosome. Although the exosome pathway has been well characterized in budding yeast (a species which lacks both a Ro ortholog and an RNA interference pathway), far less is known about its substrates and function in animal cells. We are examining how these pathways intersect to reduce expression of aberrant and potentially harmful RNAs.

Selected Publications

Sim, S., Weinberg, D.E., Fuchs, G., Choi, K., Chung, J. and Wolin, S.L. The subcellular distribution of an RNA quality control protein, the Ro autoantigen, is regulated by noncoding Y RNA binding. Mol. Biol. Cell 20, 1555-64 (2009)

Wurtmann, E.J. and Wolin, S.L. RNA under attack: cellular handling of RNA damage. Crit. Rev. Biochem. Mol. Biol. 44, 34-49 (2009)

Wurtmann, E.J. and Wolin, S.L. A role for a bacterial ortholog of the Ro autoantigen in starvation-induced rRNA degradation, Proc. Natl. Acad. Sci. USA 107, 4022-7 (2010)

Hamill, S.J., Wolin, S.L. and Reinisch, K.M. Structure and function of the polymerase core of TRAMP, a RNA surveillance complex. Proc. Natl. Acad. Sci. USA 107, 15045-50 (2010)

Kucera, N.J., Hodsdon, M.E., and Wolin, S.L. An intrinsically disordered C-terminus allows the La protein to assist the biogenesis of diverse noncoding RNA precursors. Proc. Natl. Acad. Sci. USA 108, 1308-1313 (2011)

Last Updated 7/27/11 myc