A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration

Abstract

Emerging evidence suggests that intron-detaining transcripts (IDTs) are a nucleus-detained and polyadenylated mRNA pool for cell to quickly and effectively respond to environmental stimuli and stress. However, the underlying mechanisms of detained intron (DI) splicing are still largely unknown. Here, we suggest that post-transcriptional DI splicing is paused at Bact 29 state, an active spliceosome but not catalytically primed, which depends on SNIP1 (Smad Nuclear Interacting Protein 1) and RNPS1 (a serine-rich RNA binding protein) interaction. RNPS1 and Bact component preferentially dock at DIs and the RNPS1 docking is sufficient to trigger spliceosome pausing. Haploinsufficiency of Snip1 attenuates neurodegeneration and globally rescues IDT accumulation caused by a previously reported mutant U2 snRNA, a basal spliceosomal component. Snip1 conditional knockout in cerebellum decreases DI splicing efficiency and causes neurodegeneration. Therefore, we suggest that SNIP1 and RNPS1 form a molecular brake for the spliceosome pausing, and that its misregulation contributes to neurodegeneration.

Pre-mRNA splicing order is predetermined and maintains splicing fidelity across multi-intronic transcripts

“…We found that moderate depletion of U2 snRNA levels changed splicing order in many genes. Interestingly, when we reanalyzed nanopore sequencing data from the cerebella of U2 snRNA mutant ( NMF291 -/- ) mice 48 , we found a similar co-occurrence of RIs and SEs (Extended Data Fig. 5G-H), indicating that splicing order is partially determined by the spliceosome and that splicing fidelity is disrupted when splicing order changes in vivo .…”

“…F) Distribution of the number of reads with SE, RI, both or neither in direct RNA sequencing data from control or U2 snRNA KD, for all the genes included in the SE and RI co-occurrence analysis shown in Figure 4D. G) Number of genes showing co-occurrence of SE(s) and RI(s) in transcriptome-wide cDNA-PCR nanopore sequencing data from WT and NMF291 -/- (U2 snRNA mutant) mice 48 . The x-axis categories are the same as in Figure 4D.…”