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An active role for splicing in 3′‐end formation

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Abstract When intron‐defined splicing was replaced by exon‐defined splicing in the evolution of higher eukaryotes, the splicing apparatus had to rely on the cleavage/polyadenylation (CP) apparatus for help in defining the 3′‐terminal exon. The 3′‐terminal exon‐definition complex that resulted consists of splicing factors on the upstream 3′ splice site (ss) interacting with CP factors on the downstream poly(A) signal. A speculative model for assembly of this processing complex proposes several discrete steps. First, the splicing factor, U2AF65, interacts with the CP factor, CFIm. Then, CFIm is displaced from U2AF65 by the poly(A) polymerase during a remodeling step. Finally, the U2 snRNP interacts with CPSF in a step resembling spliceosomal A‐complex formation. The result is mutual enhancement of both splicing and CP for the exon. In contrast, when the poly(A) signal is preceded by a 5′ rather than a 3′ ss, competition replaces cooperation. Thus, a poly(A) site in an intron must compete with the upstream 5′ ss for pairing with the 3′ ss further upstream, across the presumptive exon. If the poly(A) site wins the competition, a terminal exon is defined. But if the 5′ ss wins (by defining the upstream exon as internal, followed by pairing with a 3′ ss across the downstream intron), then the poly(A) site is suppressed. The U1 snRNP obviously participates in this competition through its role in splice site pairing. However, the U1 snRNP can also bind elsewhere in the transcript, apart from splice sites, to regulate CP by direct interaction with the CP factors. WIREs RNA 2011 2 459–470 DOI: 10.1002/wrna.68 This article is categorized under: RNA Processing > 3' End Processing

Recognition of introns and exons in preparation for processing. (a) Pairing of splice sites across an intron. (b) Initial pairing across the exons, followed by remodeling to define the intron. (c) Definition of a 3′‐terminal exon.

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Competition between a 5′ splice site (ss) and a poly(A) site to define a composite exon. (a) The 5′ ss wins. (b) The poly(A) site wins. (c) They both win.

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Major RNA sequence elements and protein factors involved in definition of a 3′‐terminal exon.30–33 A speculative correspondence between the establishment of individual splicing–cleavage/polyadenylation (CP) connections and the known ATP‐dependent recruitment of U2 snRNP to the branch point is shown (see text). Canonical poly(A) site cleavage factors are shown in green, and canonical splicing factors are shown in yellow. Adjacent factors interact with each other, and the interactions between splicing factors and cleavage factors thought to be responsible for coupling are indicated by red arrows. The figure is not meant to imply that all of the illustrated interactions can simultaneously coexist. Only factors that are discussed in the text are shown.

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