Sandra L. Wolin, M.D., Ph.D.
Sandra Wolin studies the biogenesis, function and turnover of noncoding RNAs. Her laboratory has identified proteins that recognize misfolded and otherwise defective RNAs. By studying a bacterial ortholog of one such protein, the ring-shaped Ro60 autoantigen, they discovered that this protein is tethered by noncoding “Y RNA” to a ring-shaped nuclease, forming a double-ringed ribonucleoprotein machine specialized for structured RNA degradation. The laboratory is characterizing this new RNA degradation machine, identifying additional roles for Ro60 and Y RNA in both human cells and bacteria, and uncovering other pathways by which defective and damaged RNAs are recognized and degraded.
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 noncoding RNAs can accumulate as a result of mutations, transcriptional errors and processing mistakes. In addition, some forms of environmental stress, such as exposure to oxidants and ultraviolet light, result in RNA damage, yet little is known of the mechanisms by which these RNAs are recognized and handled.
One pathway that we study involves ncRNA-protein complexes known as Ro60 ribonucleoproteins (RNPs). These RNPs were discovered because they 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, some archaea and ~5% of bacteria. As we found that mice lacking Ro60 develop a disease resembling systemic lupus erythematosus, Ro60 may be important for preventing autoimmunity. 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 RNA degradation machine specialized for structured RNA degradation. Interestingly, Ro60 contributes to survival of both mammalian cells and some bacteria in the presence of stresses, such as ultraviolet light, that damage nucleic acids. Our current goals are to define this new RNA degradation machine in mechanistic detail and to uncover additional roles for Ro60 and Y RNAs in both mammalian cells and bacteria.
We recently discovered a new noncoding RNA surveillance pathway in mammalian cells. In these experiments, we collaborated with Alice Telesnitsky (University of Michigan) to study how retroviruses such as the human immunodeficiency virus (HIV-1) assemble in the cytoplasm of infected cells. In addition to packaging their own genomes into virions, all retroviruses encapsidate specific cellular noncoding RNAs. We discovered that retroviruses package these RNAs from a previously unknown pathway in which newly made RNAs are exported to the cytoplasm for degradation. We are characterizing this new RNA surveillance pathway in molecular detail and determining how the packaged RNAs contribute to retrovirus replication.
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 can alter RNA pools. For example, UV irradiation causes RNA-protein crosslinks and increases transcription of retrotransposons and satellite RNAs. In addition, many common chemotherapeutics, such as mitomycin C and bleomycin, affect RNA populations. By uncovering novel mechanisms by which cells deal with the effects of RNA damage and adapt RNA pools during stress, our work has the potential to advance our understanding of the paths that lead to cancer and to increase knowledge as to how chemotherapeutic agents function.
Selected Recent Publications
- Science Translational Medicine. 10: eaan2306, 2018. [ Journal Article ]
- Chemical Reviews. 118: 4422-4447, 2018. [ Journal Article ]
- RNA. 22: 1228-38, 2016. [ Journal Article ]
- Genes Dev. 29: 646-657, 2015. [ Journal Article ]
- Cell. 153: 166-177, 2013. [ Journal Article ]
Dr. Wolin received her A.B. in Biochemical Sciences from Princeton University, her M.D. from the Yale School of Medicine and her Ph.D. degree from the Department of Biochemistry and Biophysics at Yale University. She carried out postdoctoral training with Peter Walter at the University of California San Francisco, where she devised an early ribosome profiling method. 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 Chief of the newly formed RNA Biology Laboratory. She is an elected Fellow of the American Association for the Advancement of Science and the American Academy of Microbiology.
|Cedric Belair Ph.D.||Research Fellow|
|Marco Boccitto Ph.D.||Postdoctoral Fellow (CRTA)|
|Xinguo Chen, Ph.D.||Staff Scientist|
|Kevin J. Hughes||Predoctoral Fellow (Graduate Student)|
|Yuanyuan Leng Ph.D.||Postdoctoral Fellow (Visiting)|
|Lily E. O’Connor Ph.D.||Postdoctoral Fellow (CRTA)|
|Hongmarn Park Ph.D.||Postdoctoral Fellow (Visiting)|
|Soyeong Sim Ph.D.||Staff Scientist|
Mar 28, 2018
CCR scientists have discovered that a protein produced by bacteria that naturally inhabit our bodies may trigger the autoimmune disease lupus. The results of the study could unveil an entirely new set of drug targets for treating lupus and other autoimmune diseases. Read more…
July 2017: Cedric Belair has won a FARE Award. Congratulations, Cedric!