ELAV Links Paused Pol II to Alternative Polyadenylation in the Drosophila Nervous System

Oktaba, Katarzyna; Zhang, Wei; Lotz, Thea S.; Jun, David Jayhyun; Lemke, Sandra B.; Ng, Samuel; Esposito, Emilia; Levine, Michael; Hilgers, Valérie

doi:10.1016/j.molcel.2014.11.024

Cited by 92 publications

(108 citation statements)

References 42 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…An alternative route to bind target genes has been suggested through recruitment at the promoter and deposition by elongating RNA polymerase II (Pol II) (73). Our data from using heterologous promoters for expressing ewg and nrg reporters, however, argue against this possibility for these genes but might affect a minority of large genes (40,48,74).…”

Section: Discussionmentioning

confidence: 88%

Concentration and Localization of Coexpressed ELAV/Hu Proteins Control Specificity of mRNA Processing

Zaharieva

Haussmann

Bräuer

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

bNeuronally coexpressed ELAV/Hu proteins comprise a family of highly related RNA binding proteins which bind to very similar cognate sequences. How this redundancy is linked to in vivo function and how gene-specific regulation is achieved have not been clear. Analysis of mutants in Drosophila ELAV/Hu family proteins ELAV, FNE, and RBP9 and of genetic interactions among them indicates that they have mostly independent roles in neuronal development and function but have converging roles in the regulation of synaptic plasticity. Conversely, ELAV, FNE, RBP9, and human HuR bind ELAV target RNA in vitro with similar affinities. Likewise, all can regulate alternative splicing of ELAV target genes in nonneuronal wing disc cells and substitute for ELAV in eye development upon artificially increased expression; they can also substantially restore ELAV's biological functions when expressed under the control of the elav gene. Furthermore, ELAV-related Sex-lethal can regulate ELAV targets, and ELAV/Hu proteins can interfere with sexual differentiation. An ancient relationship to Sex-lethal is revealed by gonadal expression of RBP9, providing a maternal fail-safe for dosage compensation. Our results indicate that highly related ELAV/Hu RNA binding proteins select targets for mRNA processing through alteration of their expression levels and subcellular localization but only minimally by altered RNA binding specificity. RNA binding proteins (RBPs) are key regulators of gene expression. Through regulation of alternative splicing and polyadenylation, they expand the proteome and control spatiotemporal expression by affecting mRNA transport, turnover, localization, and translatability (1, 2). In the brain, alternative mRNA processing is particularly abundant and substantially contributes to the complexity of this organ (3, 4). Many RBPs comprise highly related gene families, but they seem to discriminate only marginally between short cognate binding sequences (5). Although redundancy can be evolutionarily stable over extended periods of time (6), it is not clear if highly related RBPs act redundantly in vivo, regulating mostly the same genes in the same biological processes, or if they have diverged such that they regulate genes involved in different biological processes. Detailed analysis of the functions of highly related RBPs in animal models is required to decipher the underlying mechanisms of how highly related RBPs achieve target specificity.ELAV (embryonic-lethal abnormal visual system)/Hu proteins comprise a family of RBPs broadly coexpressed in the nervous system and widely used neuronal markers (7,8). ELAV/Hu proteins are prototype RBPs which harbor three highly conserved RNA recognition motifs (RRMs), whereby the first two RRMs are arranged in tandem and the third RRM is separated by a less conserved hinge region. Humans have four ELAV/Hu protein-encoding genes (HuB, HuC, HuD, and HuR), while Drosophila has three (elav, fne, and Rbp9), which derive from a common ancestor but have duplicated independently in vertebrates ...

show abstract

Section: Discussionmentioning

confidence: 88%

Concentration and Localization of Coexpressed ELAV/Hu Proteins Control Specificity of mRNA Processing

Zaharieva

Haussmann

Bräuer

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Defects in the cotranscriptional assembly of CPF complexes as a result of changes in transcription kinetics at the 3 ′ ends of genes may allow competition between poly(A) sites as they emerge from the elongating polymerase, therefore providing a greater opportunity for the use of distal cleavage sites. A model in which Seb1-dependent poly(A) site selection is mechanistically linked to transcription elongation kinetics is supported by recent studies showing that RNAPII pausing influences the choice between APA sites (Fusby et al 2015;Oktaba et al 2015). Furthermore, definition of a minimal downstream element (DSE) important for RNAPII pausing in S. pombe (Aranda and Proudfoot 1999) previously identified an 18-base-pair (bp) region that contains two copies of the pentanucleotide ATGTA, which is similar to the Seb1 RNA-binding motif determined by CRAC (Fig.…”

Section: Seb1 Controls Poly(a) Site Selectionmentioning

confidence: 96%

The Nrd1-like protein Seb1 coordinates cotranscriptional 3′ end processing and polyadenylation site selection

et al. 2016

View full text Add to dashboard Cite

Termination of RNA polymerase II (RNAPII) transcription is associated with RNA 3 ′ end formation. For coding genes, termination is initiated by the cleavage/polyadenylation machinery. In contrast, a majority of noncoding transcription events in Saccharomyces cerevisiae does not rely on RNA cleavage for termination but instead terminates via a pathway that requires the Nrd1-Nab3-Sen1 (NNS) complex. Here we show that the Schizosaccharomyces pombe ortholog of Nrd1, Seb1, does not function in NNS-like termination but promotes polyadenylation site selection of coding and noncoding genes. We found that Seb1 associates with 3 ′ end processing factors, is enriched at the 3 ′ end of genes, and binds RNA motifs downstream from cleavage sites. Importantly, a deficiency in Seb1 resulted in widespread changes in 3 ′ untranslated region (UTR) length as a consequence of increased alternative polyadenylation. Given that Seb1 levels affected the recruitment of conserved 3 ′ end processing factors, our findings indicate that the conserved RNA-binding protein Seb1 cotranscriptionally controls alternative polyadenylation.

show abstract

“…Furthermore, recent studies have provided evidence that the effect of some RNA-binding proteins, such as ELAV, on PAS selection is linked to the promoter and RNAP II pausing (Oktaba et al 2015).…”

Section: Regulation Of Pas Recognitionmentioning

confidence: 99%

The end of the message: multiple protein–RNA interactions define the mRNA polyadenylation site

2015

View full text Add to dashboard Cite

The key RNA sequence elements and protein factors necessary for 3 ′ processing of polyadenylated mRNA precursors are well known. Recent studies, however, have significantly reshaped current models for the protein-RNA interactions involved in poly(A) site recognition, painting a picture more complex than previously envisioned and also providing new insights into regulation of this important step in gene expression. Here we review the recent advances in this area and provide a perspective for future studies.

show abstract

ELAV Links Paused Pol II to Alternative Polyadenylation in the Drosophila Nervous System

Cited by 92 publications

References 42 publications

Concentration and Localization of Coexpressed ELAV/Hu Proteins Control Specificity of mRNA Processing

Concentration and Localization of Coexpressed ELAV/Hu Proteins Control Specificity of mRNA Processing

The Nrd1-like protein Seb1 coordinates cotranscriptional 3′ end processing and polyadenylation site selection

The end of the message: multiple protein–RNA interactions define the mRNA polyadenylation site

Contact Info

Product

Resources

About