Regulatory mechanisms in the recycling phase of the spliceosome cycle: combining the human and zebrafish systems

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Nuclear pre-mRNA splicing requires more than 100 protein factors as well as five small nuclear RNAs (snRNAs), which cooperate in the three stages of the spliceosome cycle: assembly, splicing catalysis, and recycling. Here we focus on the recycling phase, specifically on the protein factor p110, which is required for efficient U4/U6 snRNP recycling and which we have identified and previously characterized both in the human and zebrafish systems. We will use a combination of the human and zebrafish systems, thereby further establishing zebrafish as a valuable new model system in the splicing field. Specific aims are, first, to investigate the contributions of p110 and the LSm proteins in U4/U6 snRNP recycling; second, to identify genes and splicing targets affected by p110 deficiency; third, to characterize the network of coregulated components of the recycling phase; and fourth, to identify new recycling factors. In sum, this project addresses not only the mechanistic and regulatory aspects of snRNP recycling, but also the important question of how defects in a general splicing factor can result in very specific phenotypes, which is relevant for our molecular understanding of human disease.