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AUF1 regulation of coding and noncoding RNA

Advanced Review

Gerald M. Wilson, Aerielle E. Matsangos, Elizabeth J.F. White

Published Online: Sep 13 2016

DOI: 10.1002/wrna.1393

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AUF1 is a family of four RNA‐binding proteins (RBPs) generated by alternative pre‐messenger RNA (pre-mRNA) splicing, with canonical roles in controlling the stability and/or translation of mRNA targets based on recognition of AU‐rich sequences within mRNA 3′ untranslated regions. However, recent studies identifying AUF1 target sites across the transcriptome have revealed that these canonical functions are but a subset of its roles in posttranscriptional regulation of gene expression. In this review, we describe recent developments in our understanding of the RNA‐binding properties of AUF1 together with their biochemical implications and roles in directing mRNA decay and translation. This is then followed by a survey of newly discovered activities for AUF1 proteins in control of miRNA synthesis and function, including miRNA assembly into microRNA (miRNA)‐loaded RNA‐induced silencing complexes (miRISCs), miRISC targeting to mRNA substrates, interplay with an expanding network of other cellular RBPs, and reciprocal regulatory relationships between miRNA and AUF1 synthesis. Finally, we discuss recently reported relationships between AUF1 and long noncoding RNAs and regulatory roles on viral RNA substrates. Cumulatively, these findings have significantly expanded our appreciation of the scope and diversity of AUF1 functions in the cell, and are prompting an exciting array of new questions moving forward. WIREs RNA 2017, 8:e1393. doi: 10.1002/wrna.1393 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Turnover and Surveillance > Regulation of RNA Stability Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

RNA domains contributing to high‐affinity binding of p37^AUF1 to RNA substrates. Green arrows denote base‐specific contacts to AU‐rich RNA sequences, while purple arrows show nonspecific contacts upstream of the nucleating U‐rich domain. Protein contacts with the 5′‐domain are also required for AUF1‐induced remodeling of local RNA structure. (Adapted from Ref .)

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Assembly of AUF1 ribonucleoproteins (RNPs). Initial binding between an AUF1 dimer (orange) and an RNA substrate (green) generates an RNP complex with a P₂R stoichiometry concomitant with adoption of a locally condensed RNA structure (center). Recruitment of a subsequent p37^AUF1 or p40^AUF1 dimer (top right) occurs with low affinity and maintains the condensed RNA fold. However, subsequent dimer binding events on p42^AUF1 or p45^AUF1 RNPs (bottom right) occur with high affinity and induce extended RNA conformations. (Adapted from Ref .)

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Domain organization of AUF1 isoforms. All contain tandem RNA recognition motif (RRM) domains, each with characteristic ribonucleoprotein (RNP)‐2 and RNP‐1 sequence motifs (red boxes), followed by a short glutamine‐rich domain. Isoform‐specific sequences encoded by alternatively spliced exons 2 (yellow) and 7 (blue) are indicated.

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Distribution and overlap of RNA‐binding sites recognized by AUF1 and/or HuR resolved by photoactivatable ribonucleoside‐enhanced crosslinking and immunoprecipitation (PAR‐CLIP) studies. The pie chart at right summarizes the locations of RNA targets recognized by both trans‐factors. (Adapted from Ref .)

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Functional and regulatory interrelationships between AUF1 and microRNAs (miRNAs). Major pathways described in the text are indicated by red arrows: (a) positive and negative consequences of AUF1 on miRNA‐loaded RNA‐induced silencing complex (miRISC) recruitment to specific target sites on mRNA substrates, (b) AUF1‐enhanced miRNA loading into RISCs, (c) suppression of miRNA synthesis by AUF1‐targeted degradation of DICER mRNA, and (d) miRNA‐directed control of AUF1 expression.

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