The minor and major spliceosome interact to regulate alternative splicing around minor introns

Olthof, Anouk M.; White, Alisa K.; Lee, Madisen F.; Chakroun, Almahdi; Aleem, Alice K. Abdel; Rousseau, Justine; Magnani, Cinzia; Campeau, Philippe M.; Kanadia, Rahul N.

doi:10.1101/2020.05.18.101246

Cited by 2 publications

(3 citation statements)

References 68 publications

(107 reference statements)

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“…The observed reliance of viruses on MIG-Ps prompted us to explore whether MIG-Ps could be targeted through minor spliceosome inhibition. To this end, we sought to identify MIG transcripts that respond to minor spliceosome inhibition with either elevated minor intron retention or alternative splicing (7, 26) as a consequence of inhibitor treatment or pathogenic mutations. We obtained 114 responsive MIG-Ps from different datasets including HEK-293T cells treated with morpholinos against U12, U6atac and U4atac snRNA that inhibit the minor spliceosome ( Data S1) .…”

Section: Resultsmentioning

confidence: 99%

“…S3B , highlighting the relevance of these responsive MIGs. Focusing on MIGs that were responsive to the disruption of the minor spliceosome through pathogenic variants in spliceosome components (7, 26), we identified 334 MIGs with increased minor intron retention from samples of individuals with Roifman syndrome, Microcephalic Osteodysplastic Primordial Dwarfism Type I and Myelodysplastic syndrome ( Data S1 ). Notably, most of MIG-Ps that were responsive to minor intron inhibition were also affected in the context of these diseases ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Retention and alternative splicing of minor introns was evaluated in three RNAseq datasets where the minor spliceosome was inhibited (7, 26) (GSE96616). Reads were aligned to the mm10 or hg38 genome using Hisat2, followed by extraction of the uniquely mapped reads (41).…”

Section: Methodsmentioning

confidence: 99%

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Minor intron containing genes: Achilles’ heel of viruses?

Wuchty

White

Olthof

et al. 2022

Preprint

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The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed the world's unpreparedness to deal with the emergence of novel pathogenic viruses, pointing to the urgent need to identify targets for broad-spectrum antiviral strategies. Here, we report that proteins encoded by Minor Intron-containing Genes (MIGs) are significantly enriched in datasets of cellular proteins that are leveraged by SARS-CoV-2 and other viruses. Pointing to a general gateway for viruses to tap cellular machinery, MIG-encoded proteins (MIG-Ps) that react to the disruption of the minor spliceosome are most important points of viral attack, suggesting that MIG-Ps may pan-viral drug targets. While contemporary anti-viral drugs shun MIG-Ps, we surprisingly found that anti-cancer drugs that have been repurposed to combat SARS-CoV-2, indeed target MIG-Ps, suggesting that such genes can potentially be tapped to efficiently fight viruses.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Minor intron containing genes: Achilles’ heel of viruses?

Wuchty

White

Olthof

et al. 2022

Preprint

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Study of the RNA splicing kinetics via in vivo 5-EU labeling

Bolikhova,

Buyan,

Mariasina

et al. 2024

RNA

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Splicing, a process of intron removal from eukaryotic RNA transcripts, is an important step of gene expression in all eukaryotes. Splice sites might be used with different efficiency giving rise to alternative splicing products. At the same time, splice sites might be utilised at a variable rate. We used 5-ethynyl uridine labelling to sequence a nascent transcriptome of HeLa cells and deduce the rate of splicing for each donor and acceptor splice site. The following correlation analysis allowed us to assess a correspondence of primary transcript features with the rate of splicing. Some dependencies we revealed were anticipated, such as splicing rate decrease with a decreased complementarity of donor splice site to U1 and acceptor sites to U2 snRNAs, or an acceleration of donor site usage if an upstream acceptor site is located at a shorter distance. Other dependencies were more surprising, like a negative influence of a distance to the 5' end on the rate of acceptor splicing site utilization, or the differences in splicing rate between long, short and RBM17-dependent introns. We also observed a deceleration of last intron splicing with an increase of the distance to the polyA site, which might be explained by a cooperativity of the splicing and polyadenylation. In addition, we performed the analysis of splicing kinetics of SF3B4 knockdown cells which suggested the impairment of U2 snRNA recognition step. As a result, we deconvoluted the effects of several examined features on the splicing rate into a single regression model. The data obtained here are useful for further studies in the field as it provides general splicing rate dependencies as well as helps justify the existence of slowly removed splice sites, e.g. to ensure alternative splicing.

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The minor and major spliceosome interact to regulate alternative splicing around minor introns

Cited by 2 publications

References 68 publications

Minor intron containing genes: Achilles’ heel of viruses?

Minor intron containing genes: Achilles’ heel of viruses?

Study of the RNA splicing kinetics via in vivo 5-EU labeling

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