Mechanisms coordinating ELAV/Hu mRNA regulons

Simone, Laura E; Keene, Jack D.

doi:10.1016/j.gde.2012.12.006

Cited by 130 publications

(119 citation statements)

References 80 publications

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“…The configuration of HuR-binding sites in CENPN exon 12, with two centrally located strong binding sites and additional (potentially weaker) binding sites along the exon (Supplementary Fig. 6), is consistent with the ability of HuR to cooperatively bind at multiple sites along RNA and to multimerize 44 , which could conceivably favour the recognition of this large ALE exon by various mechanisms. For example, it might bring closer the 3 0 -splice site and the polyA site.…”

Section: Discussionsupporting

confidence: 70%

A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

et al. 2014

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Alternative 3 0 -terminal exons, which use intronic polyadenylation sites, are generally less conserved and expressed at lower levels than the last exon of genes. Here we discover a class of human genes, in which the last exon appeared recently during evolution, and the major gene product uses an alternative 3 0 -terminal exon corresponding to the ancestral last exon of the gene. This novel class of alternative 3 0 -terminal exons are downregulated on a large scale by doxorubicin, a cytostatic drug targeting topoisomerase II, and play a role in cell cycle regulation, including centromere-kinetochore assembly. The RNA-binding protein HuR/ ELAVL1 is a major regulator of this specific set of alternative 3 0 -terminal exons. HuR binding to the alternative 3 0 -terminal exon in the pre-messenger RNA promotes its splicing, and is reduced by topoisomerase inhibitors. These findings provide new insights into the evolution, function and molecular regulation of alternative 3 0 -terminal exons.

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Section: Discussionsupporting

confidence: 70%

A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

et al. 2014

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“…Unlike sRIP-seq, which only allows analysis of small RNAs (Ͻ35 nt), PAR-CLIP-seq can demonstrate binding to any RNA, regardless of length. The binding of AGO2 was compared to HuR, which has an affinity for AU-rich elements found within the 3= untranslated region of many mRNAs and tends to stabilize mRNAs, whereas AGO2 is a translational repressor (78). Meta-analysis of PAR-CLIP-seq signal across all tRNA genes showed strong enrichment for sense tRNA sequence compared to HuR (Fig.…”

Section: Human Argonaute 2 Binds To Actively Transcribed Trna Genesmentioning

confidence: 99%

Argonaute 2 Binds Directly to tRNA Genes and Promotes Gene Repression in cis

Woolnough

Atwood

Giles

2015

Molecular and Cellular Biology

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To further our understanding of the RNAi machinery within the human nucleus, we analyzed the chromatin and RNA binding of Argonaute 2 (AGO2) within human cancer cell lines. Our data indicated that AGO2 binds directly to nascent tRNA and 5S rRNA, and to the genomic loci from which these RNAs are transcribed, in a small RNA-and DICER-independent manner. AGO2 chromatin binding was not observed at non-TFIIIC-dependent RNA polymerase III (Pol III) genes or at extra-TFIIIC (ETC) sites, indicating that the interaction is specific for TFIIIC-dependent Pol III genes. A genome-wide analysis indicated that loss of AGO2 caused a global increase in mRNA expression level among genes that flank AGO2-bound tRNA genes. This effect was shown to be distinct from that of the disruption of DICER, DROSHA, or CTCF. We propose that AGO2 binding to tRNA genes has a novel and important regulatory role in human cells. The RNA interference (RNAi) machinery has several important functions that are conserved from fission yeast to humans. In the cytoplasm of eukaryotic cells, Argonaute proteins promote degradation and/or translational repression of specific mRNAs through tethering by a complementary small RNA (1). The nuclear functions of the RNAi machinery appear to be diverse across species and include roles in promoting heterochromatin formation, regulating alternative splicing, and promoting insulator function (2-5). The ability of both Argonaute 1 (AGO1) and AGO2 to alter splicing in human cells depends upon small RNAs derived from exonic sequence, which tether Argonaute proteins to nascent transcripts (3, 6). Tethering of each Argonaute protein was shown to be capable of recruiting a histone lysine methyltransferase, which altered the RNA polymerase II (Pol II) elongation rate and thus facilitated alternative splicing. This interaction between Argonaute proteins and the transcriptional apparatus is conserved in Drosophila melanogaster (7).Despite the similarities between Argonaute proteins, AGO2 is the only human Argonaute protein believed to have the endonuclease activity (Slicer) due to a unique amino-terminal region (8-10), and Ago2 but not Ago1 gene deletions are embryonic lethal in mice (11). AGO2 was shown to promote transcriptional gene silencing in a microRNA (miRNA)-dependent manner (12) and to affect nucleosome occupancy at certain transcription start sites through interaction with the SWI/SNF complex (13). Furthermore, AGO1 has been shown to interact with actively transcribed genes and enhancer regions (14, 15). Recent work has identified expanded binding capabilities of AGO2, which include binding to longer RNAs such as pre-miRNAs (65 to 75 nucleotides [nt]) and full-length tRNAs (ϳ75 nt) (16)(17)(18)(19)(20). To wit, AGO2 was recently shown to functionally interact with DICER in human nuclei but was unable to load duplex small interfering RNA (siRNA), indicating that nuclear RNAi processes may proceed through a mechanism distinct from that observed in the cytoplasm (21). These findings indicate that AGO2 may have roles beyo...

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“…The common view is that HuR can globally repress the degradative/inhibitory effect of miRNAs on the target mRNAs, through a direct competition for the binding sites. Indeed, when binding sites for miRNAs and HuR are proximal, HuR (and probably other RBPs) can either block or displace the miRNP complex, allowing mRNA targets to be stabilized (for review, see Simone and Keene 2013). Still, there does not appear to be a single general mechanism by which HuR antagonizes miRNPs: For example, HuR has been shown to actually decrease mRNA stability and translation of c-myc mRNA by the recruiting of let-7 miR and RISC complex (Kim et al 2009).…”

Section: Discussionmentioning

confidence: 99%

“…While these sequences are known to be destabilizing for the RNAs that contain them, the binding of HuR and HuD increases the stability of the target mRNAs and sometimes activates their translation (Jain et al 1997). Thus, HuR protein appears to be one of the few RBPs found to stabilize ARE-and URE-containing mRNAs under most conditions (Simone and Keene 2013).…”

Section: Introductionmentioning

confidence: 99%

RNA-binding protein HuR and the members of the miR-200 family play an unconventional role in the regulation of c-Jun mRNA

Vecchio

Vito

Saunders

et al. 2016

RNA

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Post-transcriptional gene regulation is a fundamental step for coordinating cellular response in a variety of processes. RNA-binding proteins (RBPs) and microRNAs (miRNAs) are the most important factors responsible for this regulation. Here we report that different components of the miR-200 family are involved in c-Jun mRNA regulation with the opposite effect. While miR-200b inhibits c-Jun protein production, miR-200a tends to increase the JUN amount through a stabilization of its mRNA. This action is dependent on the presence of the RBP HuR that binds the 3 ′ UTR of c-Jun mRNA in a region including the mir-200a binding site. The position of the binding site is fundamental; by mutating this site, we demonstrate that the effect is not micro-RNA specific. These results indicate that miR-200a triggers a microRNA-mediated stabilization of c-Jun mRNA, promoting the binding of HuR with c-Jun mRNA. This is the first example of a positive regulation exerted by a microRNA on an important oncogene in proliferating cells.

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Mechanisms coordinating ELAV/Hu mRNA regulons

Cited by 130 publications

References 80 publications

A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

Argonaute 2 Binds Directly to tRNA Genes and Promotes Gene Repression in cis

RNA-binding protein HuR and the members of the miR-200 family play an unconventional role in the regulation of c-Jun mRNA

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