hnRNP A1 and hnRNP H can collaborate to modulate 5′ splice site selection

Fisette, Jean-François; Toutant, Johanne; Dugré-Brisson, Samuel; DesGroseillers, Luc; Chabot, Benoît

doi:10.1261/rna.1890310

Cited by 58 publications

(55 citation statements)

References 57 publications

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“…Here we firstly have demonstrated the up-regulation of hnRNP D, hnRNP K and hnRNP H1 and the down-modulation of hnRNP H3 and of 3 different proteins, all recognized as hnRNP H1, inside the nucleus of APL-derived NB4 cells induced to complete their maturation with ATRA. Considering the known roles for these proteins in hematopoietic cells, all related to the regulation of mRNA stability [35][36][37][38][39][40], our data are consistent with the acquisition of a differentiated phenotype by tumoral promyelocytes as a consequence of ATRA administration.…”

Section: Discussionsupporting

confidence: 84%

Nuclear proteome analysis reveals a role of Vav1 in modulating RNA processing during maturation of tumoral promyelocytes

Bertagnolo¹,

Grassilli²,

Petretto³

et al. 2011

Journal of Proteomics

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Section: Discussionsupporting

confidence: 84%

Nuclear proteome analysis reveals a role of Vav1 in modulating RNA processing during maturation of tumoral promyelocytes

Bertagnolo¹,

Grassilli²,

Petretto³

et al. 2011

Journal of Proteomics

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“…However, there is also evidence that the presence of multiple sites flanking a 59ss can repress it by the formation of looping interactions mediated by the glycine-rich domain (Blanchette and Chabot 1999;Nasim et al 2002), which may also involve interactions with hnRNP H (Fig. 4E; Fisette et al 2010). The formation of loops does not prevent binding of U1 snRNPs but prevents further spliceosome assembly for unknown reasons (Nasim et al 2002).…”

Section: Effects and Mechanisms Of Competitionmentioning

confidence: 99%

Pick one, but be quick: 5′ splice sites and the problems of too many choices

2013

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Splice site selection is fundamental to pre-mRNA splicing and the expansion of genomic coding potential. 59 Splice sites (59ss) are the critical elements at the 59 end of introns and are extremely diverse, as thousands of different sequences act as bona fide 59ss in the human transcriptome. Most 59ss are recognized by base-pairing with the 59 end of the U1 small nuclear RNA (snRNA). Here we review the history of research on 59ss selection, highlighting the difficulties of establishing how basepairing strength determines splicing outcomes. We also discuss recent work demonstrating that U1 snRNA:59ss helices can accommodate noncanonical registers such as bulged duplexes. In addition, we describe the mechanisms by which other snRNAs, regulatory proteins, splicing enhancers, and the relative positions of alternative 59ss contribute to selection. Moreover, we discuss mechanisms by which the recognition of numerous candidate 59ss might lead to selection of a single 59ss and propose that protein complexes propagate along the exon, thereby changing its physical behavior so as to affect 59ss selection.Questions about the mechanisms by which 59 splice sites (59ss) are selected are deeply rooted in the history of research on pre-mRNA splicing. Identification of the sequences associated with 59ss triggered the first key insights into splicing mechanisms, efforts that are reflected now in the widespread use of genomic methods to quantify the contributions of other sequences and their cognate factors. The first factors shown to modulate alternative splicing affected 59ss selection, and the difficulties of working out the molecular mechanisms involved provided a foretaste of the complexities awaiting investigations into other regulatory proteins. Despite the many insights resulting from such studies over the years, it is clear that our conceptual frameworks are not yet adequate. New ideas and models are needed for studies on splice site selection. One purpose of this review is to emphasize that developing new ideas may involve first the challenge of uprooting commonsense but unsubstantiated preconceptions hidden in established models.The 59ss is involved in both steps of splicing. In the first step, the 29-hydroxyl group of the branchpoint adenosine attacks the phosphodiester bond at the 59ss and displaces the 59 exon; in the second step, the 39-hydroxyl group of the 59 exon attacks the phosphodiester bond at the 39 splice site (39ss) and displaces the lariat intron. Splicing was discovered just before new, gel-based DNA-sequencing methods transformed molecular biology. Thus, although the original discoveries were made without the benefit of sequence information (Berget et al. 1977;Chow et al. 1977), sequences emerged rapidly thereafter and revealed clear similarities among 59ss. Moreover, the ''consensus'' sequence (comprising, at each position, the nucleotide most commonly found there) was complementary to the sequence at the 59 end of U1 small nuclear RNA (snRNA), which immediately suggested a mechanism for recognition of t...

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“…Most of these proteins contain at least one RNA recognition motif (RRM) that is responsible for providing target specificity (11). Depending on the site of binding, SR proteins can also promote exon skipping, and hnRNPs can promote exon inclusion (17,26). Alternative splicing is also regulated by several other factors not related to SR proteins and hnRNPs.…”

mentioning

confidence: 99%

TIA1 Prevents Skipping of a Critical Exon Associated with Spinal Muscular Atrophy

Singh

Seo

Ottesen

et al. 2011

Molecular and Cellular Biology

111

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Prevention of skipping of exon 7 during pre-mRNA splicing of Survival Motor Neuron 2 (SMN2) holds the promise for cure of spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Here, we report T-cell-restricted intracellular antigen 1 (TIA1) and TIA1-related (TIAR) proteins as intron-associated positive regulators of SMN2 exon 7 splicing. We show that TIA1/TIAR stimulate exon recognition in an entirely novel context in which intronic U-rich motifs are separated from the 5 splice site by overlapping inhibitory elements. TIA1 and TIAR are modular proteins with three N-terminal RNA recognition motifs (RRMs) and a C-terminal glutamine-rich (Q-rich) domain. Our results reveal that any one RRM in combination with a Q domain is necessary and sufficient for TIA1-associated regulation of SMN2 exon 7 splicing in vivo. We also show that increased expression of TIA1 counteracts the inhibitory effect of polypyrimidine tract binding protein, a ubiquitously expressed factor recently implicated in regulation of SMN exon 7 splicing. Our findings expand the scope of TIA1/TIAR in genome-wide regulation of alternative splicing under normal and pathological conditions.Current estimates suggest that 95 to 100% of human genes with two or more exons are alternatively spliced, affecting all major aspects of cellular metabolism under normal and pathological conditions (12, 42). The mechanism of alternative splicing involves a complex combinatorial control in which exonic and intronic splicing enhancers (ESEs and ISEs, respectively), and silencers (ESSs and ISSs, respectively) play significant roles. In general, serine-and arginine-rich (SR) proteins promote exon inclusion through interactions with ESEs, whereas heteronuclear ribonucleoproteins (hnRNPs) promote exon exclusion through interactions with ESSs and ISSs (13, 34). Most of these proteins contain at least one RNA recognition motif (RRM) that is responsible for providing target specificity (11). Depending on the site of binding, SR proteins can also promote exon skipping, and hnRNPs can promote exon inclusion (17,26). Alternative splicing is also regulated by several other factors not related to SR proteins and hnRNPs. In addition, RNA structures that directly or indirectly affect spliceosome assembly and catalytic core formation could modulate the outcome of splicing (42, 47).The splicing reaction calls for the highest degree of precision since a shift in splicing position by 1 nucleotide could have devastating consequences (12). The biggest challenge in our understanding of alternative splicing emanates from our inability to fully comprehend the combinatorial control exerted by cis elements. Using functional or genomic approaches, a vast majority of studies have concentrated on deciphering the nature of cis elements located within exons (6,27,61,63,66). Very few studies have been dedicated to intronic cis elements, mostly focusing on the regions that flank exonic sequences (59,65,66,69). Recent genome-wide analyses of intronic sequences revealed significant ...

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hnRNP A1 and hnRNP H can collaborate to modulate 5′ splice site selection

Cited by 58 publications

References 57 publications

Nuclear proteome analysis reveals a role of Vav1 in modulating RNA processing during maturation of tumoral promyelocytes

Nuclear proteome analysis reveals a role of Vav1 in modulating RNA processing during maturation of tumoral promyelocytes

Pick one, but be quick: 5′ splice sites and the problems of too many choices

TIA1 Prevents Skipping of a Critical Exon Associated with Spinal Muscular Atrophy

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