Interactions between the U2 snRNP and SAGA reveal new links between co‐transcriptional RNA splicing and chromatin modification

Abstract

Recent studies have shown that mRNA splicing can occur co‐transcriptionally. The next key challenge is to identify the mechanisms by which specific factors couple the two reactions. We have discovered that Gcn5, which encodes the HAT activity of the SAGA, and other components of SAGA that support its catalytic activity, have functional interactions with the genes encoding the heterodimeric U2 snRNP proteins Msl1 and Lea1. ChIP analysis has revealed that Gcn5, and particularly its HAT activity, is required for co‐transcriptional recruitment of Msl1 and Lea1 to pre‐mRNA. Consistent with a role for Gcn5 in co‐transcriptional splicing, Gcn5 protein and Gcn5‐dependent histone acetylation are enriched in intron‐containing genes. These results have led us to examine how the activity of the SAGA complex affects ATP‐dependent rearrangements of the U2 snRNP that are critical for branchpoint recognition. A genetic analysis has revealed surprising interactions between the DExH/D box protein Prp5, which hydrolyzes ATP to remodel the U2 snRNP and facilitate branchpoint recognition, and components of SAGA. A lethal mutation in PRP5 that eliminates ATP‐binding is suppressed when components of the SAGA complex are deleted, thereby for the first time linking SAGA with a catalytic activity that drives spliceosomal rearrangements.(Supported by NSF CAREER grant MCB 0448010 and NRSA predoctoral fellowship 5F31 GM078745)