Sandra L. Wolin, M.D., Ph.D.

Professor of Cell Biology and Molecular Biophysics & Biochemistry
Wolin lab website Phone: (203) 737-4439 Lab: (203) 737-4426 Fax: (203) 737-1761 e-mail: sandra.wolin@yale.edu		Department of Cell Biology Yale Universtiy School of Medicine 333 Cedar Street PO Box 208002 New Haven, CT 06520-8002 <Courier Address> 295 Congress Avenue, BCMM 154B (Lab: BCMM 139/141) New Haven, CT 06519-1418

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Our laboratory studies how RNA molecules fold into intricate structures, how cells recognize and handle defective RNAs and the importance of RNA quality control for cell physiology and disease. In mammalian cells, yeast and bacteria, we focus on proteins and RNA-protein complexes that play critical roles in these processes. Our work has revealed unexpected connections between RNA misfolding, cell survival after radiation damage and autoimmune disease.

The Ro protein: a ring-shaped protein that binds misfolded RNAs in its central cavity
In one project, we study a protein called Ro, which binds misfolded RNAs that are targeted for decay. Together with Karin Reinisch, we showed that Ro is shaped like a donut, with the ends of misfolded RNAs bound inside the central hole. Interestingly, the binding of misfolded RNAs to Ro is likely regulated by noncoding RNAs called Y RNAs. Moreover, the Ro protein is part of a novel mechanism by which both mammalian cells and certain bacteria survive stresses such as irradiation with ultraviolet light. Amazingly, mice lacking Ro develop an autoimmune disease that resembles systemic lupus erythematosus in patients, suggesting that the normal function of Ro is important for preventing autoimmunity. We are characterizing the various functions of Ro in both mouse and bacterial cells.

Uncovering novel RNA quality control components in yeast
In a second effort, we are using biochemistry and genetics in yeast to identify novel components of RNA quality control pathways and to understand how known quality control pathways interface with RNA chaperones. One focus is the La protein, which binds many newly synthesized noncoding RNAs and functions as an "RNA chaperone" to assist small RNA folding and RNA-protein complex assembly.

Figure 1:  Structure of the Ro protein.  Ro is shaped like a doughnut with a central hole.  In this space-filling representation, positively charged surfaces are colored blue and negatively charged surfaces are red.  The 3’ single-stranded ends of misfolded RNA insert through the hole, which may assist in their subsequent degradation by exonucleases.

Selected Publications

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Chen, X., Wurtmann, E.J., Van Batavia, J., Zybailov, B., Washburn, M.P. and Wolin, S. L. (2007)  An orthologue of the Ro autoantigen functions in 23S rRNA maturation in D. radiodurans. Genes & Dev. 21, 1328-1339.

Reinisch KM and Wolin SL. (2007) Emerging Themes in Noncoding RNA Quality Control.  Curr. Opin. Struct. Biol. 17, 209-14.

Fuchs G, Stein AJ, Fu C, Reinisch KM and Wolin SL. (2006)  Structural and Biochemical Basis for Misfolded RNA Recognition by the Ro Protein. Nat. Struct. Mol. Biol., 13, 1002-1009.

Copela LA, Chakshusmathi, G, Sherrer RL, and Wolin SL. (2006)  The La Protein Functions Redundantly with tRNA Modification Enzymes to Ensure tRNA Structural Stability.  RNA 12, 644-54.

Wolin SL and Reinisch KM. (2006)  The Ro 60 kDa Autoantigen Comes into Focus:  Interpreting Epitope Mapping Experiments on the Basis of Structure.  Autoimmunity Reviews 5, 367-372.

Stein AJ, Fuchs G, Fu C, Wolin SL, Reinisch KM. (2005)  Structural Insights into RNA Quality Control: The Ro Autoantigen Binds Misfolded RNAs via its Central Cavity. Cell 121: 529-539.

Dong G, Chakshusmathi G, Wolin SL, Reinisch K. (2004)  Structure of the La Motif: A Winged Helix Domain Mediates RNA Binding Via a Conserved Aromatic Patch. EMBO J. 23: 1000-1007.

Chen X and Wolin SL. (2004)  The Ro 60 kDa Autoantigen: Insights Into Cellular Function And Role In Autoimmunity. J. Mol. Med. 82: 232-239.

Fernandez C, Pannone BK, Chen X, Fuchs G, Wolin SL. (2004)  An Lsm2-Lsm7 Complex Associates with the Yeast Small Nucleolar RNA snR5. Mol. Biol. Cell 15: 2842-52.

Chakshusmathi G, Kim SD, Rubinson DA, and Wolin SL. (2003)  A La Protein Requirement for Efficient Pre-tRNA Folding.  EMBO Journal 22: 6562-6572.
 
Chen X, Smith JD, Shi H, Yang DD, Flavell RA, Wolin SL (2003) The Ro 60 kDa Autoantigen Binds Misfolded U2 Small Nuclear RNAs and Assists Mammalian Cell Survival Following Ultraviolet Irradiation.  Curr Biol. 13: 2206-2211.
 
Xue D, Shi H, Smith JD, Chen X, Noe DA, Cedervall T, Yang DD, Eynon E, Brash DE, Kashgarian M, Flavell RA, Wolin SL (2003)  A Lupus-like Syndrome Develops in Mice Lacking the Ro 60 kDa Protein, a Major Lupus Autoantigen. Proc Natl Acad. Sci USA 100: 7503-7508.