Structural studies of the spliceosome: emerging insights into diversity and regulatory mechanisms

The spliceosome is a complex macromolecular machine that catalyses the essential cellular process of precursor mRNA (pre-mRNA) splicing. In the past decade, high-resolution structures for numerous stable spliceosome assembly intermediates became available, providing a structural framework for the basic splicing mechanism. However, the field still lags behind in mechanistic understanding of the precise trajectories of individual splicing factors, the regulation and organisation of splicing within the cellular context, and the mechanisms underlying splicing quality control and its links to human disease. In this review, we highlight how recent structural studies have bridged some of these knowledge gaps and brought forward our mechanistic understanding of pre-mRNA splicing. We discuss recent insights into the exon-definition problem, the role of assembly factors in small ribonucleoprotein particle (snRNP) biogenesis, spliceosome-associated quality control and the U12-dependent splicing pathway. We also provide our perspective on the future development of the field.