Auto-regulatory feedback by RNA-binding proteins

Müller-McNicoll, Michaela; Roßbach, Oliver; Hui, Jingyi; Medenbach, Jan

doi:10.1093/jmcb/mjz043

Cited by 105 publications

(89 citation statements)

References 116 publications

(137 reference statements)

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“…Interestingly, the cross-regulation, although at the splicing level, was previously reported for pairs of other homologous RNA-binding proteins [43], such as hnRNPD and D-like protein [44]. Regarding Y-box binding proteins and translational control, the ability of YB-3 to inhibit YB-1 or YB-3 mRNA translation is still questionable.…”

Section: Discussionmentioning

confidence: 95%

YB-3 substitutes YB-1 in global mRNA binding

et al. 2020

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Y-box binding proteins are DNA-and RNA-binding proteins with an evolutionarily ancient and conserved cold shock domain. The Y-box binding protein 1 (YB-1) is the most studied due to its abundance in somatic cells. YB-1 is involved in a variety of cellular processes, including proliferation, differentiation and stress response. Here, using Ribo-Seq and RIP-Seq we confirm that YB-1 binds a wide range of mRNAs and globally acts as a translation inhibitor. Surprisingly, YBX1 knockout results in only minor alterations in the expression of other genes, mostly caused by changes in RNA abundance. But YB-3 mRNA is an exception: it is better translated in the absence of YB-1, thereby producing an increased amount of YB-3 and thus suggesting that its synthesis is under YB-1 negative control. We have shown that the set of mRNAs bound to YB-3 is strikingly similar to that of YB-1, and that the mRNA-binding by YB-3 is enhanced in the absence of YB-1, resulting in a similar global reduction of translation of bound mRNAs in YB-1-null cells. Thus, YB-3 acts as a substitute for YB-1 in mRNA binding and, probably, in global translational control. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 95%

YB-3 substitutes YB-1 in global mRNA binding

et al. 2020

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“…[5][6][7], it modulates alternative polyadenylation and mRNA export and promotes translation of unspliced viral transcripts 8,9 . Recently, SRSF7 emerged as an oncogene that is overexpressed in various cancers and promotes the progression of colon and lung cancers 10-12 . Many RBPs engage in auto-regulatory feedback loops to control their levels 13 , but the mechanisms that control SRSF7 protein homeostasis and the reasons for its disruption in cancer cells are not well understood. In renal cancer cells, SRSF7 is both a target and a regulator of microRNAs miR-30a-5p and miR-181a-5p (ref.…”

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confidence: 99%

SRSF7 maintains its homeostasis through the expression of Split-ORFs and nuclear body assembly

Königs

Machado

Arnold

et al. 2020

Nat Struct Mol Biol

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Results SRSF7 overexpression induces auto-regulation.To investigate the mechanisms of SRSF7 homeostasis, we generated cell lines SRSF7 is an essential RNA-binding protein whose misexpression promotes cancer. Here, we describe how SRSF7 maintains its protein homeostasis in murine P19 cells using an intricate negative feedback mechanism. SRSF7 binding to its premessenger RNA promotes inclusion of a poison cassette exon and transcript degradation via nonsense-mediated decay (NMD). However, elevated SRSF7 levels inhibit NMD and promote translation of two protein halves, termed Split-ORFs, from the bicistronic SRSF7-PCE transcript. The first half acts as dominant-negative isoform suppressing poison cassette exon inclusion and instead promoting the retention of flanking introns containing repeated SRSF7 binding sites. Massive SRSF7 binding to these sites and its oligomerization promote the assembly of large nuclear bodies, which sequester SRSF7 transcripts at their transcription site, preventing their export and restoring normal SRSF7 protein levels. We further show that hundreds of human and mouse NMD targets, especially RNA-binding proteins, encode potential Split-ORFs, some of which are expressed under specific cellular conditions. SRSF7 binding promotes splicing of NMD-sensitive and -resistant SRSF7 isoforms. To understand the mechanism of SRSF7 auto-regulation, we examined the binding of SRSF7 protein to SRSF7 transcripts using individual-nucleotide resolution ultraviolet (UV) crosslinking and immunoprecipitation (iCLIP). We used normalized significant crosslink events (X-links, false discovery rate (FDR) < 0.05) from SRSF3 and SRSF7 iCLIP datasets of P19 cell lines without OE 8 . Similar to SRSF3, which promotes the inclusion of the PCE in SRSF7 transcripts 17 , SRSF7 showed enriched crosslinks in an extended region encompassing the PCE, its flanking introns 3a and 3b, and exons 3, 4 and 5 ( Fig. 1d). Quantification revealed that SRSF7 binds ~50-fold more to SRSF7 transcripts than SRSF3 ( Supplementary Table 1), indicating that SRSF7 has an unusual preference for its own transcripts.RNA-seq followed by quantification of junction reads revealed that SRSF7 OE promotes inclusion of either the complete PCE (460 nucleotides (nt)) or a partial PCE (107 nt) in SRSF7 transcripts ( Fig. 1e). Additionally, both PCE-flanking introns (3a and 3b) and intron 5 displayed increased read coverage, indicating that they are partly retained upon SRSF7 OE. Semiquantitative reverse transcription PCR and sequencing confirmed that SRSF7 OE caused the appearance of transcripts containing the entire PCE (SRSF7-PCE, orange asterisk), the partial PCE (SRSF7-PCE 1/4 , yellow asterisk) or the PCE in combination with both flanking introns (SRSF7-I3a+b, red asterisk) or with only intron 3b (SRSF7-I3b, green asterisk; Fig. 1f and Extended Data Fig. 1b,c). Identical isoforms were detected for endogenous and SRSF7-GFP reporter transcripts, indicating that auto-regulation operates similarly on both.All these transcripts contain PTCs and should be s...

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“…In this regard, it would be also of interest to identify and understand the function of those cis - and trans -regulatory elements that control the spatiotemporal expression of Rbm24, which may be disrupted in human diseases. In addition, due to the importance of RBP autoregulation to maintain protein homeostasis or to switch cell fate changes [ 112 ], it would be important to understand how Rbm24 self-regulates to maintain cellular homeostasis or to initiate cell differentiation during development. Furthermore, vertebrate Rbm24 also interacts and cooperates with other closely related RBPs, such as Rbm20 and Rbm38, in the regulation of cell differentiation and function [ 56 , 64 ].…”

Section: Discussionmentioning

confidence: 99%

RNA-Binding Protein Rbm24 as a Multifaceted Post-Transcriptional Regulator of Embryonic Lineage Differentiation and Cellular Homeostasis

Grifone

Shao

Saquet

et al. 2020

Cells

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RNA-binding proteins control the metabolism of RNAs at all stages of their lifetime. They are critically required for the post-transcriptional regulation of gene expression in a wide variety of physiological and pathological processes. Rbm24 is a highly conserved RNA-binding protein that displays strongly regionalized expression patterns and exhibits dynamic changes in subcellular localization during early development. There is increasing evidence that it acts as a multifunctional regulator to switch cell fate determination and to maintain tissue homeostasis. Dysfunction of Rbm24 disrupts cell differentiation in nearly every tissue where it is expressed, such as skeletal and cardiac muscles, and different head sensory organs, but the molecular events that are affected may vary in a tissue-specific, or even a stage-specific manner. Recent works using different animal models have uncovered multiple post-transcriptional regulatory mechanisms by which Rbm24 functions in key developmental processes. In particular, it represents a major splicing factor in muscle cell development, and plays an essential role in cytoplasmic polyadenylation during lens fiber cell terminal differentiation. Here we review the advances in understanding the implication of Rbm24 during development and disease, by focusing on its regulatory roles in physiological and pathological conditions.

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Auto-regulatory feedback by RNA-binding proteins

Cited by 105 publications

References 116 publications

YB-3 substitutes YB-1 in global mRNA binding

YB-3 substitutes YB-1 in global mRNA binding

SRSF7 maintains its homeostasis through the expression of Split-ORFs and nuclear body assembly

RNA-Binding Protein Rbm24 as a Multifaceted Post-Transcriptional Regulator of Embryonic Lineage Differentiation and Cellular Homeostasis

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