Trends in Biochemical Sciences
ReviewAlternative pre-mRNA splicing: the logic of combinatorial control
Section snippets
Needles in a haystack
The question of splice-site choice is intimately connected to the problem of normal recognition of constitutive splice sites6. A feature shared by both regulatory sequences and splice-site signals is that they are usually short and often degenerate. The information content of their primary sequence is therefore rather limited (Fig. 2a). Even the best computer programs are only 50% accurate in predicting actual splice sites over multiple, equally good candidate sequences that are not used.
Packing and remodelling RNA
Primary transcripts form densely packed ribonucleoprotein complexes, known as heterogeneous nuclear (hn)RNPs, by associating with a family of polypeptides known as hnRNP proteins19, 20. These are a diverse group of nuclear RNA-binding proteins that are involved in multiple functions. They contain various types of RNA-binding motifs, as well as domains rich in glycine and other amino acids (but not RS domains), which might serve in both RNA binding and protein–protein interactions. The set and
Antagonism in splice-site selection
Early biochemical studies indicated that hnRNP proteins could regulate splice-site choice13. SV40 virus large T and small t proteins are generated from the same pre-mRNA by the use of alternative 5′ splice sites. An excess of the SR protein alternative splicing factor (ASF, also known as splicing factor 2 or SF2) promoted the use of the proximal site. This observation was subsequently extended to other RNAs and SR proteins. A model that explains these observations is that under limiting
Regulatory complexes
Simple antagonism between individual hnRNP proteins and splicing factors might represent the basic operations of a more complex interplay between constitutive factors and dedicated regulators to achieve cell-type-specific splicing. The examples that follow illustrate this point.
Multiple combinatorial control
Even simple tissue-specific decisions can reveal additional layers of complexity, in which complexes assembling on different RNA elements synergize or antagonize each other. As mentioned earlier, the Src gene contains a neuron-specific 18-nucleotide exon. At least six different RNA sequences have separable effects in exon skipping and inclusion (Fig. 3b). The short exon length and binding sites for PTB flanking the exon are important for exon skipping in non-neural cells32, 46. The Src ISE
Future challenges
The realization that cell-specific patterns of processing are achieved by an elaborate interplay of signals and complexes has two important implications for future work. First, understanding regulated splicing will still require a detailed, gene-specific analysis of the contributions of multiple sequences and factors and their mutual influences in different cell types. Second, an overall picture of cell-specific splicing will require quantification of the relative levels of expression of entire
Acknowledgements
We thank Doug Black, Javier Cáceres, Tom Cooper, Benoit Chabot, Fátima Gebauer, Iain Mattaj, Jim Patton and members of our laboratories for comments on the manuscript. Because of space limitations, we have cited reviews and recent articles that include extensive references to each particular topic rather than original references. We apologize to those colleagues whose work has not been cited more directly. Work in the laboratory of C.W.J.S. is supported by grants from the Wellcome Trust,
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