Mechanisms of mRNA Recruitment into Stress Granules

ABSTRACT The integrated stress response (ISR) is an evolutionarily conserved signaling network that is activated in response to environmental stress and functions to support stress adaptation. A key part of the ISR is the stalling of global translation while allowing for the preferential translation of stress response factors. Upon stalling of global translation, mRNAs are incorporated into stress granules (SGs), which are cytoplasmic phase- separated ribonucleoprotein granules. SG transcriptome studies have revealed that the efficiency with which individual mRNAs are recruited to stress granules ranges from 1 to 95 percent, indicating a selectivity to mRNA recruitment. However, little is known about the mechanisms by which mRNAs are selectively recruited to SGs. Our lab has discovered a link between gene transcriptional state and SG incorporation, suggesting a model for mRNA recruitment that favors the incorporation of newly transcribed and exported mRNAs rather than the existing cytoplasmic mRNA population. This proposal seeks to investigate the mechanisms of mRNA recruitment to SGs at a transcriptome-wide level, examining the role of transcription and nuclear export in SG biogenesis along with assessing the contributions of newly transcribed versus existing cytoplasmic populations of mRNAs. As stress granules have been implicated in multiple diseases, insights into how the mRNA composition of SGs is determined could inform mechanisms of disease and potential therapeutics.