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Diverse regulation of 3' splice site usage - PubMed

Review

Diverse regulation of 3' splice site usage

Muhammad Sohail et al. Cell Mol Life Sci. 2015 Dec.

Abstract

The regulation of splice site (SS) usage is important for alternative pre-mRNA splicing and thus proper expression of protein isoforms in cells; its disruption causes diseases. In recent years, an increasing number of novel regulatory elements have been found within or nearby the 3'SS in mammalian genes. The diverse elements recruit a repertoire of trans-acting factors or form secondary structures to regulate 3'SS usage, mostly at the early steps of spliceosome assembly. Their mechanisms of action mainly include: (1) competition between the factors for RNA elements, (2) steric hindrance between the factors, (3) direct interaction between the factors, (4) competition between two splice sites, or (5) local RNA secondary structures or longer range loops, according to the mode of protein/RNA interactions. Beyond the 3'SS, chromatin remodeling/transcription, posttranslational modifications of trans-acting factors and upstream signaling provide further layers of regulation. Evolutionarily, some of the 3'SS elements seem to have emerged in mammalian ancestors. Moreover, other possibilities of regulation such as that by non-coding RNA remain to be explored. It is thus likely that there are more diverse elements/factors and mechanisms that influence the choice of an intron end. The diverse regulation likely contributes to a more complex but refined transcriptome and proteome in mammals.

Keywords: Alternative splicing; Evolution; RNA element; Secondary structure; Splicing factor.

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Figures

Fig. 1
Fig. 1

Diagram of pre-mRNA splicing steps and trans-acting 3′SS regulators. Shown at the top is splice sites motifs shown in different colors with consensus sequence and represented in the intron with respective colors. 5′SS (maroon line), BP (blue line), Py (green line) and 3′AG (olive line). Below is the stepwise assembly of constitutive splicing factors (ovals) for excision of intron between exon 1 (red) and exon 2 (blue). Boxes on the right list trans-acting alternative splicing factors that regulate the corresponding steps of spliceosome assembly for exon 2 splicing

Fig. 2
Fig. 2

Mechanisms of splicing repression at 3′SS. The regulated exon shown in the middle is flanked by introns and exons. Splicing patterns in bold lines indicate the outcome of regulation. Purple oval represents one of the repressors listed in purple boxes on the right side that are involved in the regulation through respective mechanisms indicated on the left side. a Splicing repression through cis-acting elements within Py. The location of a major class of silencers within 3′SS overlaps with Py. These elements recruit trans-acting factors to inhibit U2AF binding to Py through competition (i). b Splicing repression through cis-acting element insertions between Py and 3′AG. A group of 3′SS silencers is uniquely positioned between Py and 3′AG (red line in intron). Such elements also inhibit U2AF mainly through steric hindrance (ii) caused by specific binding of repressors. c Splicing repression through cis-acting elements near BP. Some 3′SS silencers are located near or in overlap with BP. The binding of trans-acting factors to these elements results in inhibition of U2 snRNP interaction with BP either through competition (i) or steric hindrance (ii). d Inhibition of weakened 3′SS by competition of downstream stronger 3′SS. The weakening of upstream 3′SS by intronic binding of U2AF (purple oval) results in inhibition by competing 3′SS (iii). e Splicing repression through ‘RNA secondary structures or loops’. In some cases Py binding trans-acting alternative splicing factors interact cooperatively with another RNA-binding protein bound to downstream intron (purple ovals and arrows). This interaction results in looping out (iv) of the regulated exon and interferes with U1 and U2AF binding to its splice sites leading to inhibition of exon definition. RNA secondary structures also trap 3′SS motifs in a similar way but without proteins to repress splicing

Fig. 3
Fig. 3

Mechanisms of splicing activation at 3′SS. Individual activators are shown as brown ovals and they are listed on the right side in brown boxes along with respective mechanisms for the regulation shown on the left side. a Splicing activation through inhibition of a repressor by enhancer motifs in Py. The binding of a trans-acting factor to an enhancer motif within Py results in competition with a repressor (yellow oval/PTB) binding (I) and facilitates U2AF binding to Py to promote 3′SS usage. b–d Splicing activation through cis-acting elements located at different positions within 3′SS. The locations of these elements are within Py (b), near BP (c) or between Py and 3′AG (red line) (d). A common feature of 3′SS regulation by these elements is their recognition by respective trans-acting factors for interaction with U2AF or U2 snRNA (II) to facilitate their RNA-binding leading to activation of splicing. e Activation of 3′SS by repression of downstream 3′SS. The repression of a downstream 3′SS through binding of PTB to Py inhibiting U2AF results in activation of a competing 3′SS (III)

Fig. 4
Fig. 4

Mechanisms of weaker 3′SS activation through RNA secondary structures/loops. a Base-pairing interaction between intronic RNA motifs. The activation of a 3′SS through looping of pre-mRNA can also result from base-pairing of an intronic motif (purple line) with a second motif located near regulated splice site (orange line). These motifs are referred to as docking or selector sites as indicated on the right side. The formation of such secondary structures or loops (IV) promotes 3′SS usage. b Interaction between a complex of splicing factors and 3′SS spliceosome components. In this mechanism a protein complex (red oval) binds to an intron upstream of regulated exon and interacts with spliceosome proteins of 3′SS to promote its usage. SR proteins shown in red box on the right side form such known complexes. c Cooperative interaction of a splicing factor. This mechanism of pre-mRNA looping involves the binding of a trans-acting splicing factor (red oval) near intron ends. Examples of such factors are shown in red box on the right side. The cooperative interaction between the factors bound near intron ends creates a loop of spanning intronic sequence that brings its splice sites along with their spliceosomal components in close proximity to activate 3′SS

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