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

Our laboratory studies how noncoding RNAs function, how cells recognize and eliminate defective RNAs, and how failure to remove 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 the surveillance mechanisms by which misfolded, damaged or other aberrant RNAs are recognized and eliminated.

Our entry point into this research area was our study of the La and Ro60 autoantigens, two clinically important targets of the immune system in patients suffering from two rheumatic diseases, systemic lupus erythematosus and Sjögren’s disease. We discovered that La was a molecular chaperone for noncoding RNAs and that Ro60 recognized misfolded noncoding RNAs. Our recent studies have revealed that Ro60 and La function synergistically to unfold misfolded noncoding RNAs, giving these RNAs additional chances to fold correctly. Many different noncoding RNAs are complexed with La and Ro60 in cells, suggesting that the roles of this RNA chaperone machine may be wide-ranging.

In all studied organisms, Ro60 also binds noncoding RNAs called Y RNAs. Our studies have revealed that one role of Y RNAs is to tether Ro60 to other proteins to create specialized RNPs. Our current goals are to uncover additional roles for La, Ro60 and Y RNAs in mammalian cells. As Ro60 and Y RNAs are present in some bacteria, we also seek to decipher the functions of the bacterial RNPs. We are also studying ways in which these and other RNA surveillance pathways and RNA chaperones contribute to normal cell physiology and prevent diseases such as cancer.

Relevance to cancer

There is now good evidence that both RNA chaperones and RNA surveillance pathways prevent aberrant cellular RNAs from activating innate immune sensors. Two prominent sensors, RIG-I and MDA5, recognize double-stranded RNA produced during virus infection and initiate an antiviral response that includes production of inflammatory cytokines and interferon. It is also now known that activation of these sensors by endogenous RNAs can influence tumor growth. For example, mutations in surveillance pathways can result in upregulation of aberrant RNAs that, by triggering RNA sensors, stimulate the immune system to fight tumors. Conversely, upregulation of surveillance pathways, by removing RNAs that would otherwise activate these sensors, can help tumor cells prevent an innate immune response. By uncovering novel mechanisms by which cells recognize and remove excess, misfolded, defective and damaged RNAs, our work could advance understanding of the ways in which these RNA chaperones and RNA surveillance pathways influence the tumor microenvironment.

Dr. Wolin earned her A.B. in Biochemical Sciences from Princeton University, her M.D. from the Yale School of Medicine and her Ph.D. from the Department of Molecular Biophysics and Biochemistry at Yale University. After postdoctoral training at the University of California, San Francisco, she returned to the Yale School of Medicine as an Assistant Professor and rose to the rank of Professor in the Departments of Cell Biology and Molecular Biophysics and Biochemistry. From 2014-2017, she served as Director of the Yale Center for RNA Science and Medicine. She joined the NCI in 2017 as the inaugural Chief of the newly formed RNA Biology Laboratory and Head of the NCI RNA Biology Initiative. She is an elected Fellow of the American Association for the Advancement of Science (2013), the American Academy of Microbiology (2014), the American Academy of Arts and Sciences (2023) and the National Academy of Sciences (2024).