Alternative pre-mRNA splicing: the logic of combinatorial control

doi:10.1016/S0968-0004(00)01604-2

Trends in Biochemical Sciences

Volume 25, Issue 8, 1 August 2000, Pages 381-388

https://doi.org/10.1016/S0968-0004(00)01604-2 Get rights and content

Abstract

Alternative splicing of mRNA precursors is a versatile mechanism of gene expression regulation that accounts for a considerable proportion of proteomic complexity in higher eukaryotes. Its modulation is achieved through the combinatorial interplay of positive and negative regulatory signals present in the RNA, which are recognized by complexes composed of members of the hnRNP and SR protein families.

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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Trends in Biochemical Sciences

ReviewAlternative pre-mRNA splicing: the logic of combinatorial control

Abstract

Section snippets

Needles in a haystack

Packing and remodelling RNA

Antagonism in splice-site selection

Regulatory complexes

Multiple combinatorial control

Future challenges

Acknowledgements

Neuron

Cell

Trends Genet.

Am. J. Hum. Genet.

Curr. Opin. Genet. Dev.

Cell

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

J. Biol. Chem.

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

Curr. Biol.

Curr. Opin. Cell Biol.

Mol. Cell

Trends Biochem. Sci.

Cell

Curr. Opin. Genet. Dev.

Mol. Cell

Mol. Cell

Mol. Cell

Alternative splicing and programmed cell death

Proc. Soc. Exp. Biol. Med.

Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation

Annu. Rev. Genet.

Finding splice sites within a wilderness of RNA

RNA

The structure and function of proteins involved in mammalian pre-mRNA splicing

Annu. Rev. Biochem.

Intron recognition comes of age

Nat. Struct. Biol.

Review
Alternative pre-mRNA splicing: the logic of combinatorial control