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Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response.

Author(s): Rath, Sneha; Prangley, Eliza; Donovan, Jesse; Demarest, Kaitlin; Wingreen, Ned; et al

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Abstract: Viral and endogenous double-stranded RNA (dsRNA) is a potent trigger for programmed RNA degradation by the 2-5A/RNase L complex in cells of all mammals. This 2-5A-mediated decay (2-5AMD) is a conserved stress response switching global protein synthesis from homeostasis to production of interferons (IFNs). To understand this mechanism, we examined 2-5AMD in human cells and found that it triggers polysome collapse characteristic of inhibited translation initiation. We determined that translation initiation complexes and ribosomes purified from translation-arrested cells remain functional. However, spike-in RNA sequencing (RNA-seq) revealed cell-wide decay of basal mRNAs accompanied by rapid accumulation of mRNAs encoding innate immune proteins. Our data attribute this 2-5AMD evasion to better stability of defense mRNAs and positive feedback in the IFN response amplified by RNase L-resistant molecules. We conclude that 2-5AMD and transcription act in concert to refill mammalian cells with defense mRNAs, thereby "prioritizing" the synthesis of innate immune proteins.
Publication Date: 2019
Electronic Publication Date: 4-Sep-2019
Citation: Rath, Sneha, Prangley, Eliza, Donovan, Jesse, Demarest, Kaitlin, Wingreen, Ned S, Meir, Yigal, Korennykh, Alexei. (2019). Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response.. Molecular cell, 75 (6), 1218 - 1228.e6. doi:10.1016/j.molcel.2019.07.027
DOI: doi:10.1016/j.molcel.2019.07.027
ISSN: 1097-2765
EISSN: 1097-4164
Pages: 1218 - 1228.e6
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Molecular Cell
Version: Author's manuscript

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