The Nucleolar Detention Center: a Hub of Long Noncoding RNAs that Imprison Proteins During Stress

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The Nucleolar Detention Center: A Hub of Long Noncoding RNA that Imprison Proteins During Stress NIGMS R01 (R01GM115342) Grant Renewal Project Summary The ability of cells to adapt to a wide variety of stress conditions plays a critical role in various physiological and pathological settings, including development, cancer and neurological disorders. In this current grant cycle, we reported the surprising discovery of stress-induced low complexity noncoding RNA derived from stimuli-specific loci of the ribosomal intergenic spacer (rIGSRNA); an enigmatic region of the human genome historically dismissed as “junk” DNA. We showed that low complexity rIGSRNA activate a physiological amyloidogenic program that converts the nucleolus into Amyloid Bodies (A-bodies): a molecular prison of immobilized proteins in an amyloid-like state. This rather unusual post-translational regulatory pathway enables cells to rapidly and reversibly store an array of endogenous proteins in A-bodies and enter quiescence in response to severe environmental insults. While many membrane-less compartments have been described as liquid-like (e.g. stress granules, P-bodies, germ cell granules), our discovery of A-bodies provided evidence of an amyloidogenic process that can physiologically transition biological matter to a solid-like state. In this grant renewal, we will show that the ribosomal intergenic spacer produces a large family of low complexity RNA that differ in their length, dinucleotide content and repetitive arrangement. These variable properties of rIGSRNA operate as architectural determinants that recruit common and distinct proteins to seed condition-specific A-bodies. We will also provide preliminary data that A-bodies enclose groups of polyadenylated RNA that may be involved in stress recovery. Conceptually, this NIGMS-funded research has uncovered an adaptive program that relies on a class of inducible low complexity RNA molecules to control cellular fate by assembling our newly-discovered nuclear membrane-less organelle: A-bodies. Based on these aforementioned rationales, we hypothesize that “Low complexity rIGSRNA activate physiological amyloidogenic programs that assemble stress-specific A-bodies”. In the Specific Aims, we will: 1. Uncover dinucleotide repeat motifs in rIGSRNA that seed A-bodies; 2. Explore the mechanisms that confer A-body identity; and 3. Examine processes involved in polyadenylated RNA storage by A-bodies. Our proposed work on low complexity rIGSRNA will open new lines of investigation on the physiological role of simple long intergenic dinucleotide repeats observed across the genome, but commonly ignored as non-functional DNA/RNA. In addition, the observation that low complexity RNA activate an amyloidogenic process of physiological liquid-to-solid transition will provide alternative insights into pathological amyloidogenesis involved in many human diseases. Finally, our planned experiments on polyadenylated RNA storage by A-bodies will unveil new regulatory pathways in RNA biology. Our research program is of general interest to scientists studying nuclear/cytoplasmic structures, cellular response to stress, long noncoding RNA biology, and physiological/pathological amyloidogenesis.