Nature Reviews Neuroscience
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Box 1 | The basics of splicing
In eukaryotes, genetic information is not continuous. Genes are transcribed into pre-messenger RNAs from which internal fragments (introns) are excised and the remaining fragments (exons) are joined together to generate mature mRNA. This process is called splicing and permits different mRNAs (and thereby different proteins) to be produced from a single pre-mRNA by regulating the choice of exons to be included in the mature transcript (alternative splicing). Newly synthesized pre-mRNA in the eukaryotic nucleus is recognized by the splicing apparatus, which includes small nuclear RNAs complexed with a multitude of proteins to form small nuclear ribonucleoproteins (snRNPs). These snRNPs associate with the pre-mRNA in an orderly way and constitute the basal machinery that mediates splicing97 (see animation online).
Although introns can vary substantially in size and sequence, they maintain several conserved motifs, most prominently dinucleotides in their 5' and 3' ends (splice-donor and splice-acceptor site, respectively) and an adenosine (A) in the branch point the initial sequence recognized in intron cleavage. These motifs are recognized by components of the splicing machinery (for example, U1 snRNP binds to the 5' splice site (SS) and U2 snRNP binds to the branch point adenosine). Recognition leads to the recruitment of other components of the spliceosome (U4/6 and U5 snRNPs), followed by rearrangement in the base pairing with RNA and excision of the intron. The mechanism by which exons are differentiated from introns is obscure, particularly in cases in which exon splicing involves exons that are skipped (cassette exons), mutually exclusive (alternatively spliced) or contain more than one splice site (5' or 3').
Alternative splicing regulation is mediated by interactions of the splicing machinery with further protein factors that enhance or repress the spliceosome. Understanding of this process has been derived largely from Drosophila melanogaster, in which protein factors that regulate splicing bind to specific RNA target elements present within regulated exons or in adjacent intronic sequences. Both enhancers and repressors of splicing have been identified. In addition, tissue-specific, positive and negative factors have recently been found to regulate neuron-specific alternative splicing in mammalian cells.
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