Alternative polyadenylation determines the functional landscape of inverted Alu repeats.

Mol Cell

Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea; Graduate School of Engineering Biology, KAIST, Daejeon 34141, Korea; KAIST Institute for BioCentury, KAIST, Daejeon 34141, Korea; KAIST Institute for Health Science and Technology (KIHST), KAIST, Daejeon 34141, Korea; BioProcess Engineering Research Center and BioInformatics Research Center, KAIST, Daejeon 34141, Korea. Electronic address:

Published: March 2024

Inverted Alu repeats (IRAlus) are abundantly found in the transcriptome, especially in introns and 3' untranslated regions (UTRs). Yet, the biological significance of IRAlus embedded in 3' UTRs remains largely unknown. Here, we find that 3' UTR IRAlus silences genes involved in essential signaling pathways. We utilize J2 antibody to directly capture and map the double-stranded RNA structure of 3' UTR IRAlus in the transcriptome. Bioinformatic analysis reveals alternative polyadenylation as a major axis of IRAlus-mediated gene regulation. Notably, the expression of mouse double minute 2 (MDM2), an inhibitor of p53, is upregulated by the exclusion of IRAlus during UTR shortening, which is exploited to silence p53 during tumorigenesis. Moreover, the transcriptome-wide UTR lengthening in neural progenitor cells results in the global downregulation of genes associated with neurodegenerative diseases, including amyotrophic lateral sclerosis, via IRAlus inclusion. Our study establishes the functional landscape of 3' UTR IRAlus and its role in human pathophysiology.

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http://dx.doi.org/10.1016/j.molcel.2024.01.008DOI Listing

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