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Gomberg Lecture - DNA where you expect RNA: from fluorescent aptamers to stress granules

Adrian Ferre-D'Amare (NIH/NHLBI)
Monday, April 29, 2024
11:00 AM-12:15 PM
1640 Chemistry Dow Lab Map
It is generally taken for granted that DNA is a biochemically "inert", structurally sedate repository of genetic information, while RNA carries out sophisticated activities such as selective small-molecule binding and catalysis. In this lecture, I will discuss two instances where we have encountered DNA performing unexpected roles. In the first, our structural determination of the fluorogenic DNA aptamer "Lettuce" revealed a novel 4-way junctional fold that provides a binding site for its cognate fluorophore. While numerous RNA molecules capable of inducing the fluorescence (often in excess of 5000-fold) of otherwise non-fluorescent dyes have been isolated through in vitro evolution, the 3D structures of these "turn-on" aptamers rely on extensive interactions of the ribose 2'-OH. Lettuce adopts its complex fold using completely different strategies, therefore hinting that new principles of nucleic acid structure may emerge from the analysis of functional DNAs. In the second, we have discovered that DNA in the cytoplasm is essential for the eukaryotic stress response. From yeast to human, when cells encounter stressors (heat, cold, hypoxia, etc.), their initial response is the cessation of protein synthesis, and the condensation of their now ribosome-free mRNAs into large cytoplasmic bodies known as stress granules. We have recently devised new methods to purify stress granule cores from both budding yeast and mammalian (HEK293T) cells, finding that they are biochemically stable, ~200 nm particles. Analysis of their protein and RNA composition largely confirmed the results of previous reports on stress granule composition. Unexpectedly, we discovered that stress granule cores also contain double-stranded circular DNA (extrachromosomal circular DNA, eccDNA), and that their structural integrity in vitro depends on this DNA. Moreover, targeting cytoplasmic eccDNAs through CRISPR technology abrogates the ability of live yeast to form stress granules. Previous studies have found eccDNAs in all eukaryotic cells, but had not hinted at a cytoplasmic role. Our work provides a new functional connection, mediated by DNA, between the nucleus, cytoplasmic membraneless organelles, protein synthesis, and the response of eukaryotic cells to their changing environments.
Building: Chemistry Dow Lab
Event Type: Workshop / Seminar
Tags: Chemical Biology, Chemistry, Gomberg Lecture, Science
Source: Happening @ Michigan from Department of Chemistry, Chemical Biology