Mechanism of alternative splicing and its regulation

Abstract

Alternative splicing of precursor mRNA is an essential mechanism to increase the complexity of gene expression, and it plays an important role in cellular differentiation and organism development. Regulation of alternative splicing is a complicated process in which numerous interacting components are at work, including cis-acting elements and trans-acting factors, and is further guided by the functional coupling between transcription and splicing. Additional molecular features, such as chromatin structure, RNA structure and alternative transcription initiation or alternative transcription termination, collaborate with these basic components to generate the protein diversity due to alternative splicing. All these factors contributing to this one fundamental biological process add up to a mechanism that is critical to the proper functioning of cells. Any corruption of the process may lead to disruption of normal cellular function and the eventuality of disease. Cancer is one of those diseases, where alternative splicing may be the basis for the identification of novel diagnostic and prognostic biomarkers, as well as new strategies for therapy. Thus, an in-depth understanding of alternative splicing regulation has the potential not only to elucidate fundamental biological principles, but to provide solutions for various diseases.

Keywords: alternative splicing; disease; mechanism; precursor mRNA; regulation.

Figure 1.

Five main types of alternative splicing events are depicted. (A) Constitutive splicing; (B) mutually exclusive exons; (C) cassette alternative exon; (D) alternative 3′ splice site; (E) alternative 5′ splice site; and (F) intron retention.

Figure 2.

Schematic representation of the sequence elements and proteins at 5′ and 3′ exon-intron boundaries in an RNA transcript. The diagram illustrates the appropriate relative distributions of the molecules and core splicing signals with its consensus sequence in regulation of the alternative splicing. The enhancer elements [(exonic splicing enhancers (ESEs) and intronic splicing enhancers (ISEs)] are recognized by activator proteins (the SR protein family), and the silencer elements [exonic splicing silencers (ESSs) and intronic splicing silencers (ISSs)] are bound by repressor proteins [the heterogeneous nuclear ribonucleoproteins (hnRNP) protein family]. These two protein families are engaged to promote or inhibit spliceosome assembly at weak splice sites, respectively.