An active role for splicing in 3′‐end formation

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