PremRNA Splicing 2121 General Mechanisms

In addition to editing, the 5-HT2C receptor pre-mRNA undergoes alternative splicing. Alternative splicing affects an estimated 95% of human intron containing genes and is one of the most important mechanisms to increase the use of information encoded in eukaryotic genomes (Pan et al. 2008; Wang et al. 2008). The mechanism of splicing catalysis has been studied in considerable detail (Jurica and Moore 2003; Wahl et al. 2009). Critical for the catalysis are transient interactions between the pre-mRNA and five small nuclear ribonucleoprotein (snRNPs) (reviewed in Biamonti and Caceres 2009; Stark and Luhrmann 2006). The interaction is based on imperfect base complementarity between the snRNPs and the pre-mRNA (Sharp 1994).

In contrast to the constitutive splicing mechanism, it is not fully understood how splice sites, especially the alternative ones, are selected. Currently, it is not possible to accurately identify alternative spliced exons from genomic DNA sequences. The problem is that splice sites exhibit a large degree of sequence variations and only the four GU-AG nucleotides flanking the intron are conserved (Stamm et al. 2006; Thanaraj and Clark 2001). The splicing machinery needs therefore additional signals that define an exon (Robberson et al. 1990). This signal is provided by transient complexes of splicing regulatory proteins and pre-mRNA. Once these complexes have formed, they interact with components of the core spliceosome, which allows the correct identification of splice sites.

Serine-arginine-rich proteins (SR-proteins) and heterogenous ribonuclear-proteins (hnRNPs) are the major classes of proteins identified in complexes forming on pre-mRNA. These proteins bind to short degenerate sequences on the pre-mRNA. The degeneracy of the sequences allows the coding requirements of the pre-mRNA to be independent from splicing requirements. Depending on which proteins they bind, sequence elements on the pre-mRNA can act as either enhancers or silencers, which either promote or antagonize exon usage. Splicing regulatory proteins generally possess RNA-binding and protein-interaction domains that allow weak, transient binding between protein and pre-mRNA as well as among proteins that assemble on the pre-mRNA. The combination of these multiple weak interactions ultimately leads to the accurate recognition of exons by the spliceosome (Smith and Valcarcel 2000; Maniatis and Tasic 2002; Hertel 2008).

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