Increased versatility despite reduced molecular complexity: evolution, structure and function of metazoan splicing factor PRPF39

Abstract

In the yeast U1 snRNP the Prp39/Prp42 heterodimer is essential for early steps of spliceosome assembly. In metazoans no Prp42 ortholog exists, raising the question how the heterodimer is functionally substituted. Here we present the crystal structure of murine PRPF39, which forms a homodimer. Structure-guided point mutations disrupt dimer formation and inhibit splicing, manifesting the homodimer as functional unit. PRPF39 expression is controlled by NMD-inducing alternative splicing in mice and human, suggesting a role in adapting splicing efficiency to cell type specific requirements. A phylogenetic analysis reveals coevolution of shortened U1 snRNA and the absence of Prp42, which correlates with overall splicing complexity in different fungi. While current models correlate the diversity of spliceosomal proteins with splicing complexity, our study highlights a contrary case. We find that organisms with higher splicing complexity have substituted the Prp39/Prp42 heterodimer with a PRPF39 homodimer.

The U1 snRNP component RBP45d regulates temperature-responsive flowering in Arabidopsis thaliana

“…AS of PRP39 pre-mRNA was also recently observed in mammalian systems (De Bortoli et al, 2019). In the case of murine ( Mus musculus ) and human PRP39 , the inclusion of an alternative exon between exons 8 and 9 produces a PTC-containing isoform, which further leads to its degradation by NMD or production of a non-functional, truncated PRP39 protein that lacks the C terminus and thus disrupts its function as a backbone of U1 auxiliary complex.…”

“…In the case of U1 snRNP, yeast U1 auxiliary proteins associate with the U1 core in a relatively stable interaction. However, in mammals, U1 auxiliary factors only transiently interact with the core complex (Li et al, 2017; De Bortoli et al, 2019). In plants, biochemical and structural information on the U1 core and auxiliary components is limited; it is therefore unclear whether U1 auxiliary factors, including PRP39a and RBP45d, stably or transiently associate with the U1 core.…”

“…PRP39 forms homodimers in mammals, and PRP39 forms heterodimers with PRP42 in yeast, to bridge the interaction between U1 auxiliary and U1 core components (Li et al, 2017; Plaschka et al, 2018). PRP39 pre-mRNA undergoes tissue-specific AS that results in truncated PRP39 proteins that can no longer dimerize (De Bortoli et al, 2019). In this study, we discovered that, like mammalian PRP39 , AS of Arabidopsis PRP39a generates isoforms carrying PTCs in the middle of its transcripts.…”

Identification of copper death-associated molecular clusters and immunological profiles in rheumatoid arthritis

“…It is a homolog of the yeast Prp39 and Prp42 paralogs, that is tightly coupled to gene transcription and subsequent splicing processes ( 55 , 56 ). Previous studies have found that PRPF39 expression levels strongly influence in vitro splicing ( 57 ), particularly in immune cell differentiation and activation, for which regulated intron retention has been shown to play an important role in controlling gene expression and function ( 58 ). On the other hand, it was found that RA was closely related to splicing variants ( 59 , 60 ), and by examining the altered levels of splicing mechanism components and inflammatory mediators, it was found that the dysregulation of splicing mechanism components, such as SNRNP70, SNRNP200 and U2AF2, could be reversed when TNFi was intervened in vivo ( 61 ).…”

A genetic screen in Arabidopsis reveals the identical roles for RBP45d and PRP39a in 5’ cryptic splice site selection

“…It has been implicated that U1C is essential for U1 snRNP function by interacting with the Sm protein and recognizing the sequence of the 5' ss (Nelissen et al, 1994;Du and Rosbash, 2002). In contrast, yeast Saccharomyces cerevisiae U1 snRNA (568 nts) is significantly larger than mammalian U1 snRNA (De Bortoli et al, 2019), and its U1 snRNP contains seven additional U1 auxiliary proteins including Prp39, Prp40, Snu71, Snu56, Luc7, Prp42, and Nam8 (Li et al, 2017). Among these U1 auxiliary proteins, the yeast Nam8 was reported to directly bind to the uridine (U)-rich sequence downstream of the 5' ss and U1 snRNP at the same time, so as to effectively help splicing of introns with non-classical 5' ss sequences (Puig et al, 1999).…”