PT  - JOURNAL ARTICLE
AU  - Dawei Meng
AU  - Qian Zheng
AU  - Xue Zhang
AU  - Li Luo
AU  - Yichang Jia
TI  - A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration
AID  - 10.1101/2022.01.11.475943
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.11.475943
4099  - http://biorxiv.org/content/early/2022/01/12/2022.01.11.475943.short
4100  - http://biorxiv.org/content/early/2022/01/12/2022.01.11.475943.full
AB  - 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 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.Competing Interest StatementThe authors have declared no competing interest.