An Alternative Spliceosome Uses Different snRNPs to Process the Minor Class of Introns

KEY CONCEPTS
-  An alternative splicing pathway uses another set of snRNPs that comprise the U12 spliceosome.
- The target introns are defined by longer consensus sequences at the splice junctions rather than strictly according to the GU-AG or AU-AC rules.
- Major and minor spliceosomes share critical protein factors, including SR proteins.
GU-AG introns comprise the majority (more than 98%) of splice sites in the human genome. Exceptions to this case are noncanonical splice AU-AC sites and other variations. Initially, this minor class of introns was referred to as AU-AC introns compared to the major class of introns that follow the GU-AG rule during splicing. With the elucidation of the machinery for processing of both major and minor introns, it becomes clear that this nomenclature for the minor class of introns is not entirely accurate.
Guided by years of research on the major spliceosome, the machinery for processing the minor class of introns was quickly elucidated; it consists of U11 and U12 (related to U1 and U2,respectively), a common U5 shared with the major spliceosome, and the U4_atac and U6_atac snRNAs. The splicing reaction is essentially similar to that of the major class of introns, and the snRNAs play analogous roles: U11 base pairs with the 5′ splice sites; U12 base pairs with the branch point sequence near the 3′ splice site; and U4_atac and U6_atac provide analogous functionsduring the spliceosome assembly and activation of the spliceosome.
It turns out that the dependence on the type of spliceosome is also influenced by the sequences in other places in the intron, so that there are some GU-AG introns spliced by the U12-type spliceosome. A strong consensus sequence at the left end defines the U12-dependent type of intron: 5′ UAUCCUUU … PyA 3′.

In fact, most U12-dependent introns have the GU … AG termini. They have a highly conserved branch point (UCCUUPuAPy), though, which pairs with U12. This difference in branch point sequences is the primary distinction between the major and minor classes of introns. For this reason, the major class of introns is termed U2-dependent introns and the minor class is called U12-dependent introns, instead of AU-AC introns.
The two types of intron coexist in a variety of genomes, and in most cases are found in the same gene. U12-dependent introns tend to be flanked by U2-dependent introns. The phylogeny of these introns suggests that AU-AC U12-dependent introns may once have been more common, but tend to be converted to GU-AG termini, and to U2 dependence, in the course of evolution. The common evolution of the systems is emphasized by the fact that they use analogous sets of base pairing between the snRNAs and with the substrate pre-mRNA. In addition, all essential splicing factors (i.e., SR proteins) studied thus far are required for processing both U2-type and U12-type introns.
One noticeable difference between U2 and U12 types of intron is that U1 and U2 appear to independently recognize the 5′ and 3′ splice sites in the major class of introns during the formation of the E and A complexes, whereas U11 and U12 form a complex in the first place, which together contact the 5′ and 3′ splice sites to initiate the processing of the minor class of introns. This ensures that the splice sites in the minor class of introns are recognized simultaneously by the intron definition mechanism. It also avoids GA GC “confusing” the splicing machineries during the transition from exon definition to intron definition for processing the major and minor classes of introns that are present in the same gene.

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