How Are Short Exons Flanked by Long Introns Defined and Committed to Splicing?

Hollander, Dror; Naftelberg, Shiran; Lev-Maor, Galit; Kornblihtt, Alberto R.; Ast, Gil

doi:10.1016/j.tig.2016.07.003

Cited by 52 publications

(67 citation statements)

References 123 publications

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“…Perhaps the increased time required to transcribe the longer introns characteristic of exondefined transcripts affords more time for recognition (and perhaps proofreading) of exon definition complexes on upstream exons. It has also been proposed that efficient juxtaposition of exons is favored by tethering of the upstream exon definition complex to the elongating polymerase during transcription of the subsequent exon (Hollander et al 2016). Splicing factors of the SR protein family or other families may also play a role in accelerating exon definition, given our observations that particular sequence motifs are enriched in exons associated with exon definition, and previous observations that SR proteins can enhance splicing rates in mammalian systems (Long and Caceres 2009;Zhou and Fu 2013).…”

Section: Discussionmentioning

confidence: 54%

“…Progression toward splicing is thought to occur in one of two modes -either by "intron definition," in which the U1 and U2 snRNPs first interact across the intron; or "exon definition," in which U1 snRNP initially pairs with the upstream U2 snRNP across the exon, followed by rearrangement to form interactions with the downstream U2 snRNP across the intron (Berget 1995). The pairing of U1 and U2 snRNPs requires bringing these molecules into close proximity, through either passive diffusion-based contact or co-localization regulated by other splicing factors (De Conti et al 2013;Hollander et al 2016). Subsequent steps of splicing proceed in a standard fashion regardless of the splice-site recognition mode, with the formation of an intronic lariat and cleavage at the 3' splice site to complete intron excision and joining together of the flanking exons.…”

Section: Introductionmentioning

confidence: 99%

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The kinetics of pre-mRNA splicing in theDrosophilagenome: influence of gene architecture

Pai

Henriques²,

McCue

et al. 2017

Preprint

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Production of most eukaryotic mRNAs requires splicing of introns from pre-mRNA. The splicing reaction requires definition of splice sites, which are initially recognized in either intron-spanning ("intron definition") or exon-spanning ("exon definition") pairs. To understand how exon and intron length and splice site recognition mode impact splicing, we measured splicing rates genome-wide in Drosophila, using metabolic labeling/RNA sequencing and new mathematical models to estimate rates. We found that the modal intron length range of 60-70 nt represents a local maximum of splicing rates, but that much longer exon-defined introns are spliced even faster and more accurately. Surprisingly, we observed low variation in splicing rates across introns in the same gene, suggesting the presence of gene-level influences, and we identified multiple gene level variables associated with splicing rate. Together our data suggest that developmental and stress response genes may have preferentially evolved exon definition in order to enhance rates of splicing.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

The kinetics of pre-mRNA splicing in theDrosophilagenome: influence of gene architecture

Pai

Henriques²,

McCue

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

“…These initial cross-exon interactions later need to be exchanged for cross-intron interactions for proper splicing catalysis. The molecular mechanisms by which the requisite cross-intron interactions are formed after the initial cross-exon interactions are established remain a critical, yet unanswered question in the field (De Conti et al 2013; Hollander et al 2016). …”

mentioning

confidence: 99%

The power of fission: yeast as a tool for understanding complex splicing

Fair

Pleiss

2016

Curr Genet

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Pre-mRNA splicing is an essential component of eukaryotic gene expression. Many metazoans, including humans, regulate alternative splicing patterns to generate expansions of their proteome from a limited number of genes. Importantly, a considerable fraction of human disease causing mutations manifest themselves through altering the sequences that shape the splicing patterns of genes. Thus, understanding the mechanistic bases of this complex pathway will be an essential component of combating these diseases. Dating almost to the initial discovery of splicing, researchers have taken advantage of the genetic tractability of budding yeast to identify the components and decipher the mechanisms of splicing. However, budding yeast lacks the complex splicing machinery and alternative splicing patterns most relevant to humans. More recently, many researchers have turned their efforts to study the fission yeast, Schizosaccharomyces pombe, which has retained many features of complex splicing, including degenerate splice site sequences, the usage of exonic splicing enhancers, and SR proteins. Here, we review recent work using fission yeast genetics to examine pre-mRNA splicing, highlighting its promise for modeling the complex splicing seen in higher eukaryotes.

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“…The functionality of these 'splice signals' is dependent not only on their sequences but also on the context in which they are present within the pre-mRNA (2). Exonic segments flanking an intron contain a variety of splicing regulatory elements (3) including exonic splicing enhancers (ESEs) and exonic splicing silencers (ESSs) (4), both of which contain loosely conserved sequences for engagement of different RNA binding proteins and are important for regulated assembly of the spliceosome (5). One of the most studied regulators of ESE-dependent splicing activation is the serine-arginine-rich (SR) family of RNA-binding proteins that contain an N-terminal RNA-binding domain (RBD) and an Arg-Ser-rich (RS) domain at their C-terminus (6).…”

Section: Introductionmentioning

confidence: 99%

Structural disruption of exonic stem-loops immediately upstream of the intron regulates mammalian splicing

Saha

England

Fernandez

et al. 2018

Preprint

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ABSTRACTRecognition of highly degenerate mammalian splice sites by the core spliceosomal machinery is regulated by several protein factors that predominantly bind exonic splicing motifs. These are postulated to be single-stranded in order to be functional, yet knowledge of secondary structural features that regulate the exposure of exonic splicing motifs across the transcriptome is not currently available. Using transcriptome-wide RNA structural information we show that retained introns in mouse are commonly flanked by a short (≲70 nucleotide), highly base-paired segment upstream and a predominantly single-stranded exonic segment downstream. Splicing assays with select pre-mRNA substrates demonstrate that loops immediately upstream of the introns contain pre-mRNA-specific splicing enhancers, the substitution or hybridization of which impedes splicing. Additionally, the exonic segments flanking the retained introns appeared to be more enriched in a previously identified set of hexameric exonic splicing enhancer (ESE) sequences compared to their spliced counterparts, suggesting that base-pairing in the exonic segments upstream of retained introns could be a means for occlusion of ESEs. The upstream exonic loops of the test substrate promoted recruitment of splicing factors and consequent pre-mRNA structural remodeling, leading up to assembly of the early spliceosome. These results suggest that disruption of exonic stem-loop structures immediately upstream (but not downstream) of the introns regulate alternative splicing events, likely through modulating accessibility of splicing factors.

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How Are Short Exons Flanked by Long Introns Defined and Committed to Splicing?

Cited by 52 publications

References 123 publications

The kinetics of pre-mRNA splicing in theDrosophilagenome: influence of gene architecture

The kinetics of pre-mRNA splicing in theDrosophilagenome: influence of gene architecture

The power of fission: yeast as a tool for understanding complex splicing

Structural disruption of exonic stem-loops immediately upstream of the intron regulates mammalian splicing

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