CONICET | Buscador de Institutos y Recursos Humanos

Splicing is the process by which introns are removed from the precursor messenger RNA (pre-mRNA) and consecutive exons are joined, and constitutes a key step in the generation of mature mRNA molecules ready for translation. This process is carried out by the ?spliceosome?, a complex of small nuclear ribonucleoprotein particles (snRNPs) and associated proteins that assemble on pre-mRNA in a precise and stepwise manner, recognizing sequence-specific splice sites located at the intron-exon boundaries. Alternative splicing takes place when two or more splice sites compete, allowing the differential removal of specific exonic sequences from mature mRNA or inclusion of intronic ones, in a developmental stage-, sex-, or tissue-specific manner. Alternative splicing represents an extraordinary source of protein diversity as many different protein isoforms that perform distinct and even antagonistic cellular activities can be generated from a single pre-mRNA. Alternative splicing regulation is coupled to transcription and is dependent on the interaction of splicing factors with cis-acting exonic or intronic motifs termed splicing enhancers and splicing silencers. The activity of these factors is modulated by post-translational modifications, in particular by phosphorylation, which may also affect their cellular localization. Recent work has begun to unravel the molecular mechanisms by which signal transduction pathways activated by extracellular cues modulate the activity of these splicing regulators and therefore the splicing pattern of different target pre-mRNAs. Mutations that alter cis-acting splicing elements or changes in the activity of splicing regulatory proteins that compromise the accuracy of either constitutive or alternative splicing could have a profound impact on human pathogenesis, in particular in tumour development and progression. Therefore, the regulation of the splicing process is crucial to assure the proper orchestration of cellular functions within multicellular organisms.