Heterogeneous Nuclear Ribonucleoprotein Particle A/B Proteins and the Control of Alternative Splicing of the Mammalian Heterogeneous Nuclear Ribonucleoprotein Particle A1 Pre-mRNA

Chabot, Benoit; LeBel, Catherine; Hutchison, Stephen; Nasim, Faiz-ul-Hassan; Simard, Martin J.

doi:10.1007/978-3-662-09728-1_3

Cited by 42 publications

(33 citation statements)

References 113 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1E, lanes 1-4). As proposed previously for hnRNP A1 binding sites (Chabot et al 2003), the activity of a single HBS may be due to weaker hnRNP H binding sites on the pre-mRNA that provide partners for H bound to the high-affinity site. Higher concentrations of available hnRNP proteins may cause this activity, and these concentrations may vary in different extracts.…”

Section: Hnrnp H Binding Sites Modulate 59 Splice Site Selectionmentioning

confidence: 63%

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

Fisette¹,

Toutant²,

Dugré-Brisson³

et al. 2009

RNA

View full text Add to dashboard Cite

The mammalian proteins hnRNP A1 and hnRNP H control many splicing decisions in viral and cellular primary transcripts. To explain some of these activities, we have proposed that self-interactions between bound proteins create an RNA loop that represses internal splice sites while simultaneously activating the external sites that are brought in closer proximity. Here we show that a variety of hnRNP H binding sites can affect 59 splice site selection. The addition of two sets of hnRNP H sites in a model pre-mRNA modulates 59 splice site selection cooperatively, consistent with the looping model. Notably, binding sites for hnRNP A1 and H on the same pre-mRNA can similarly collaborate to modulate 59 splice site selection. The C-terminal portion of hnRNP H that contains the glycine-rich domains (GRD) is essential for splicing activity, and it can be functionally replaced by the GRD of hnRNP A1. Finally, we used the bioluminescence resonance energy transfer (BRET) technology to document the existence of homotypic and heterotypic interactions between hnRNP H and hnRNP A1 in live cells. Overall, our study suggests that interactions between different hnRNP proteins bound to distinct locations on a pre-mRNA can change its conformation to affect splicing decisions.

show abstract

Section: Hnrnp H Binding Sites Modulate 59 Splice Site Selectionmentioning

confidence: 63%

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

Fisette¹,

Toutant²,

Dugré-Brisson³

et al. 2009

RNA

View full text Add to dashboard Cite

show abstract

“…The best characterized splicing activator proteins are members of the SR protein family (Fu 1995;Graveley 2000), which bind to exonic splicing enhancers (ESEs). Well-known repressor proteins include hnRNP A1 and PTB (Wagner and Garcia-Blanco 2001;Black 2003;Chabot et al 2003), which bind to silencer elements to block spliceosome assembly. The combined expression of these factors is thought to lead to stable differences in exon inclusion between different cell types.…”

Section: ++mentioning

confidence: 99%

A consensus CaMK IV-responsive RNA sequence mediates regulation of alternative exons in neurons

Xie

Jan²,

Stoilov³

et al. 2005

RNA

View full text Add to dashboard Cite

Neurons make extensive use of alternative pre-mRNA splicing to regulate gene expression and diversify physiological responses. We showed previously in a pituitary cell line that the Ca ++ /calmodulin-dependent protein kinase CaMK IV specifically repressed splicing of the BK channel STREX exon. This repression is dependent on a CaMK IV-responsive RNA element (CaRRE) within the STREX 3 0 splice site. Here, we report that similar Ca ++ regulation of splicing, mediated by L-type calcium channels and CaM kinase IV, occurs in cultured neurons and in the brain. We identify a critical CaRRE motif (CACATNRTTAT) that is essential for conferring CaMK IV repression on an otherwise constitutive exon. Additional Ca ++ -regulated exons that carry this consensus sequence are also identified in the human genome. Thus, the Ca ++ /CaMK IV pathway in neurons controls the alternative splicing of a group of exons through this short CaRRE consensus sequence. The functions of some of these exons imply that splicing control through the CaMK IV pathway will alter neuronal activity.

show abstract

“…Current models of constitutive and a fortiori alternative splicing suggest that splice site recognition is strongly modulated by the interaction of specific exonic and intronic pre-mRNA sequences with at least two classes of nonspliceosomal nuclear RNA-binding proteins: serine-arginine-rich (SR) proteins (5-7) and heterogeneous nuclear ribonucleoproteins (8)(9)(10). These proteins interact with spliceosomal components (5-7) and either activate or prevent the use of degenerate splice sites in their vicinity.…”

mentioning

confidence: 99%

Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors

Soret

Bakkour

Maire

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

111

106

View full text Add to dashboard Cite

The prevalence of alternative splicing as a target for alterations leading to human genetic disorders makes it highly relevant for therapy. Here we have used in vitro splicing reactions with different splicing reporter constructs to screen 4,000 chemical compounds for their ability to selectively inhibit spliceosome assembly and splicing. We discovered indole derivatives as potent inhibitors of the splicing reaction. Importantly, compounds of this family specifically inhibit exonic splicing enhancer (ESE)-dependent splicing, because they interact directly and selectively with members of the serine-arginine-rich protein family. Treatment of cells expressing reporter constructs with ESE sequences demonstrated that selected indole derivatives mediate inhibition of ESE usage in vivo and prevent early splicing events required for HIV replication. This discovery opens the exciting possibility of a causal pharmacological treatment of aberrant splicing in human genetic disorders and development of new antiviral therapeutic approaches.splicing correction ͉ exonic splicing enhancer ͉ small chemicals ͉ pathologic splicing R emoval of introns from newly transcribed RNA polymerase II precursors (pre-mRNA) during splicing not only is an essential step for the expression of most genes in higher eukaryotic cells but also constitutes an important mechanism for generation of protein diversity and regulation of gene expression (1, 2). It is estimated that Ͼ70% of human genes are subjected to alternative splicing, and it is not surprising that many point mutations causing human diseases are associated with aberrant splicing (3, 4).Current models of constitutive and a fortiori alternative splicing suggest that splice site recognition is strongly modulated by the interaction of specific exonic and intronic pre-mRNA sequences with at least two classes of nonspliceosomal nuclear RNA-binding proteins: serine-arginine-rich (SR) proteins (5-7) and heterogeneous nuclear ribonucleoproteins (8-10). These proteins interact with spliceosomal components (5-7) and either activate or prevent the use of degenerate splice sites in their vicinity. Thus, binding of SR proteins to exonic splicing enhancers (ESE) through their RNA-recognition motif (RRM) promotes exon definition by recruiting constitutive factors via protein-protein interactions mediated by their arginine-serine-rich (RS) domain and prevents the action of nearby splicing silencers (4, 6, 11).Mutations causing human diseases may affect splice sites as well as regulatory sequences leading to the production of defective proteins (4, 11). Thus, targeting either the mutated sequences or the factors that bind them may prove to be a valuable strategy to correct aberrant splicing. Recently, antisense strategies targeting ESEdependent mechanisms have been used to induce skipping of exons containing nonsense mutations or, conversely, to restore exon inclusion by synthetic exon-specific effectors (bifunctional antisense peptide molecules or tailed antisense oligonucleotides) or spliceosome-mediat...

show abstract

Heterogeneous Nuclear Ribonucleoprotein Particle A/B Proteins and the Control of Alternative Splicing of the Mammalian Heterogeneous Nuclear Ribonucleoprotein Particle A1 Pre-mRNA

Cited by 42 publications

References 113 publications

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

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

A consensus CaMK IV-responsive RNA sequence mediates regulation of alternative exons in neurons

Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors

Contact Info

Product

Resources

About