The nuts and bolts of the endogenous spliceosome.

The complex life of pre-mRNA from transcription to the production of mRNA that can be exported from the nucleus to the cytoplasm to encode for proteins entails intricate coordination and regulation of a network of processing events. Coordination is required between transcription and splicing and between several processing events including 5' and 3' end processing, splicing, alternative splicing and editing that are major contributors to the diversity of the human proteome, and occur within a huge and dynamic macromolecular machine-the endogenous spliceosome. Detailed mechanistic insight of the splicing reaction was gained from studies of the in vitro spliceosome assembled on a single intron. Because most pre-mRNAs are multiintronic that undergo alternative splicing, the in vivo splicing machine requires additional elements to those of the in vitro machine, to account for all these diverse functions. Information about the endogenous spliceosome is emerging from imaging studies in intact and live cells that support the cotranscriptional commitment to splicing model and provide information about splicing kinetics in vivo. Another source comes from studies of the in vivo assembled spliceosome, isolated from cell nuclei under native conditions-the supraspliceosome-that individually package pre-mRNA transcripts of different sizes and number of introns into complexes of a unique structure, indicating their universal nature. Recent years have portrayed new players affecting alternative splicing and novel connections between splicing, transcription and chromatin. The challenge ahead is to elucidate the structure and function of the endogenous spliceosome and decipher the regulation and coordination of its network of processing activities. WIREs RNA 2017, 8:e1377. doi: 10.1002/wrna.1377 For further resources related to this article, please visit the WIREs website.