Sandra L. Wolin, M.D., Ph.D.
RNA Biology Laboratory
Building 560, Room 21-105A
Frederick, MD 21702-1201
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.
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.
Eckwahl MJ, Arnion H, Kharytonchyk S, Zang T, Bieniasz PD, Telesnitsky A, Wolin SL. Analysis of the human immunodeficiency virus-1 RNA packageome. RNA. 2016;22(8):1228-38.
Eckwahl MJ, Sim S, Smith D, Telesnitsky A, Wolin SL. A retrovirus packages nascent host noncoding RNAs from a novel surveillance pathway. Genes Dev. 2015;29(6):646-57.
Kosmaczewski SG, Edwards TJ, Han SM, Eckwahl MJ, Meyer BI, Peach S, Hesselberth JR, Wolin SL, Hammarlund M. The RtcB RNA ligase is an essential component of the metazoan unfolded protein response. EMBO Rep. 2014;15(12):1278-85.
Chen X, Sim S, Wurtmann EJ, Feke A, Wolin SL. Bacterial noncoding Y RNAs are widespread and mimic tRNAs. RNA. 2014;20(11):1715-24.
Chen X, Taylor DW, Fowler CC, Galan JE, Wang HW, Wolin SL. An RNA degradation machine sculpted by Ro autoantigen and noncoding RNA. Cell. 2013;153(1):166-77.
Related Scientific Focus Areas
Genetics and Genomics
Microbiology and Infectious Diseases
Molecular Biology and Biochemistry
This page was last updated on November 13th, 2017