High-affinity hnRNP A1 binding sites and duplex-forming inverted repeats have similar effects on 5??? splice site selection in support of a common looping out and repression mechanism

Nasim, Faiz-ul-Hassan; Hutchison, Stephen; Cordeau, Mélanie; Chabot, Benoît

doi:10.1017/s1355838202024056

Cited by 79 publications

(77 citation statements)

References 36 publications

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“…More recent findings suggest that PTB is monomeric (Simpson et al 2004;Amir-Ahmady et al 2005;Monie et al 2005), although it remains possible that weak interactions between RNA bound monomers could occur (Clerte and Hall 2006). Similar looping and propagation binding models have been proposed to explain splicing repression by hnRNPA1, and evidence for both forms of binding has been obtained in different systems (Zhu et al 2001;Nasim et al 2002). Therefore, both RNA looping and propagative binding are plausible possibilities for the cooperative binding of PTB in different model systems.…”

Section: Discussionmentioning

confidence: 77%

Repression of α-actinin SM exon splicing by assisted binding of PTB to the polypyrimidine tract

Matlin

Southby²,

Gooding³

et al. 2007

RNA

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Polypyrimidine tract binding protein (PTB) acts as a regulatory repressor of a large number of alternatively spliced exons, often requiring multiple binding sites in order to repress splicing. In one case, cooperative binding of PTB has been shown to accompany repression. The SM exon of the a-actinin pre-mRNA is also repressed by PTB, leading to inclusion of the alternative upstream NM exon. The SM exon has a distant branch point located 386 nt upstream of the exon with an adjacent 26 nucleotide pyrimidine tract. Here we have analyzed PTB binding to the NM and SM exon region of the a-actinin pre-mRNA. We find that three regions of the intron bind PTB, including the 39 end of the polypyrimidine tract (PPT) and two additional regions between the PPT and the SM exon. The downstream PTB binding sites are essential for full repression and promote binding of PTB to the PPT with a consequent reduction in U2AF 65 binding. Our results are consistent with a repressive mechanism in which cooperative binding of PTB to the PPT competes with binding of U2AF 65 , thereby specifically blocking splicing of the SM exon.

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Section: Discussionmentioning

confidence: 77%

Repression of α-actinin SM exon splicing by assisted binding of PTB to the polypyrimidine tract

Matlin

Southby²,

Gooding³

et al. 2007

RNA

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“…hnRNPs function by a wide variety of mechanisms. For example, PTB (hnRNP I) can block essential interactions between U1 and U2 snRNPs (Izquierdo et al 2005;Sharma et al 2005), whereas hnRNP A1 can inhibit splicing by binding on either side and ''looping out'' exons or by directly displacing snRNP binding (Zhu et al 2001;Nasim et al 2002). Other splicing inhibitory mechanisms may also be used by these or other repressors.…”

Section: Exonic Splicing Enhancers and Silencersmentioning

confidence: 99%

Splicing regulation: From a parts list of regulatory elements to an integrated splicing code

Wang¹,

Burge²

2008

RNA

881

761

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Alternative splicing of pre-mRNAs is a major contributor to both proteomic diversity and control of gene expression levels. Splicing is tightly regulated in different tissues and developmental stages, and its disruption can lead to a wide range of human diseases. An important long-term goal in the splicing field is to determine a set of rules or ''code'' for splicing that will enable prediction of the splicing pattern of any primary transcript from its sequence. Outside of the core splice site motifs, the bulk of the information required for splicing is thought to be contained in exonic and intronic cis-regulatory elements that function by recruitment of sequence-specific RNA-binding protein factors that either activate or repress the use of adjacent splice sites. Here, we summarize the current state of knowledge of splicing cis-regulatory elements and their context-dependent effects on splicing, emphasizing recent global/genome-wide studies and open questions.Keywords: context dependence; pre-mRNA splicing; splicing code; splicing factor; splicing regulation PRE-MRNA SPLICING Because human genes typically contain multiple introns, the process of pre-mRNA splicing is an essential step in the expression of most genes. A majority of human genes undergo alternative splicing (AS), generating multiple splicing isoforms containing different combinations of exons (Johnson et al. 2003). The effects of AS on protein products can be dramatic, e.g., producing soluble versus membranebound forms of the Fas receptor that have opposing effects on apoptosis (Cascino et al. 1995), or producing isoforms of the Drosophila fruitless protein that act to specify sexual orientation (Demir and Dickson 2005). The major forms of AS are summarized in Figure 1A. Splicing regulation has been comprehensively described in several recent reviews (Black 2003;Konarska and Query 2005;Matlin et al. 2005;Blencowe 2006;House and Lynch 2008). Here, we briefly summarize some aspects of splicing specificity and regulation before turning to our main topic of splicing regulatory elements and the rules governing their activity.The sequential phosphodiester transfer reactions involved in splicing are catalyzed by large ribonucleoprotein complexes known as spliceosomes. Containing more than 100 core proteins and five small nuclear RNAs (snRNAs U1, U2, U4, U5, and U6), spliceosomes may be the most complex machines in the cell (Zhou et al. 2002;Jurica and Moore 2003;Nilsen 2003). In addition to these core factors, additional regulatory proteins participate in the splicing of particular pre-mRNAs. Splicing of most introns is thought to occur cotranscriptionally with fairly extensive interactions between splicing factors and the core transcription machinery ( CORE SPLICING SIGNALSThree sites, the 59 splice site (59ss), the 39 splice site (39ss), and the branch point sequence (BPS), participate in the splicing reaction and are present in every intron, and thus are known as the core splicing signals. These signals are recognized multiple times during spl...

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“…Their function is to bind to the ESS to the exclusion of SR proteins. A looping out pre-mRNA leads to exonic sequestration from the rest of pre-mRNA transcript (27). HnRNPs A/B are a family of RNA-binding proteins, its diversification roles in the modulation of alternative splicing have evolved based on differing affinities for their cognate nucleic acids (28).…”

Section: Molecular Mechanisms Of Alternative Spicingmentioning

confidence: 99%

Mechanism of alternative splicing and its regulation

et al. 2014

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Abstract. Alternative splicing of precursor mRNA is an essential mechanism to increase the complexity of gene expression, and it plays an important role in cellular differentiation and organism development. Regulation of alternative splicing is a complicated process in which numerous interacting components are at work, including cis-acting elements and trans-acting factors, and is further guided by the functional coupling between transcription and splicing. Additional molecular features, such as chromatin structure, RNA structure and alternative transcription initiation or alternative transcription termination, collaborate with these basic components to generate the protein diversity due to alternative splicing.

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High-affinity hnRNP A1 binding sites and duplex-forming inverted repeats have similar effects on 5??? splice site selection in support of a common looping out and repression mechanism

Cited by 79 publications

References 36 publications

Repression of α-actinin SM exon splicing by assisted binding of PTB to the polypyrimidine tract

Repression of α-actinin SM exon splicing by assisted binding of PTB to the polypyrimidine tract

Splicing regulation: From a parts list of regulatory elements to an integrated splicing code

Mechanism of alternative splicing and its regulation

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