Structure of the activated human minor spliceosome

Bai, Rui; Wan, Ruixue; Wang, Lin; Xu, Kui; Zhang, Qiangfeng; Lei, Jianlin; Shi, Yigong

doi:10.1126/science.abg0879

Cited by 58 publications

(99 citation statements)

References 77 publications

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“…This provided a phylogenetic absence/ presence profile that was used in an unbiased genome-wide query for genes with similar phylogenetic profiles (Fig 3A). The resulting list of genes most strongly co-occurring with CENATAC was significantly enriched for components of the minor (U12-dependent) spliceosome complex, including the recently discovered SCNM1 (Bai et al, 2021) (Fig 3B, Table EV2). We thus reasoned that CENATAC may play a role in splicing by the minor spliceosome.…”

Section: Cenatac Is a Novel Component Of The Minor Spliceosomementioning

confidence: 99%

“…B GO term analysis of the genes co-occurring with CENATAC as in (A) with a correlation score of > 0.5. Note: The amount of hits and fold enrichment score were manually changed to accommodate the recently discovered SCNM1 (Bai et al, 2021). Schematics showing key assembly stages in minor intron splicing and minor tri-snRNP assembly: intron recognition (A complex) and the catalytic spliceosome (C complex).…”

Section: A-type Minor Introns Are Spliced Less Efficientlymentioning

confidence: 99%

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Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

et al. 2021

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Aneuploidy is the leading cause of miscarriage and congenital birth defects, and a hallmark of cancer. Despite this strong association with human disease, the genetic causes of aneuploidy remain largely unknown. Through exome sequencing of patients with constitutional mosaic aneuploidy, we identified biallelic truncating mutations in CENATAC (CCDC84). We show that CENATAC is a novel component of the minor (U12-dependent) spliceosome that promotes splicing of a specific, rare minor intron subtype. This subtype is characterized by AT-AN splice sites and relatively high basal levels of intron retention. CENATAC depletion or expression of disease mutants resulted in excessive retention of AT-AN minor introns in~100 genes enriched for nucleocytoplasmic transport and cell cycle regulators, and caused chromosome segregation errors. Our findings reveal selectivity in minor intron splicing and suggest a link between minor spliceosome defects and constitutional aneuploidy in humans.

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Section: Cenatac Is a Novel Component Of The Minor Spliceosomementioning

confidence: 99%

Section: A-type Minor Introns Are Spliced Less Efficientlymentioning

confidence: 99%

Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

et al. 2021

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“…The recent purified structure of the human minor spliceosome revealed six conserved amino acid residues of RBM48 that mediate the interaction of RBM48-ARMC7 protein complex with U6atac 24 . Of these, four amino acid residues are N-terminal to the conserved RRM domain of RBM48.…”

Section: Discussionmentioning

confidence: 99%

“…A combination of in vivo co-expression, Bimolecular Fluorescence Complementation (BiFC), and in vitro pull-down assays showed that maize RBM48 interacts with RGH3 and the core U2 splicing factors U2AF1 and U2AF2 24 . U2AF2 binds to the polypyrimidine tract of U2-type introns; whereas U2AF1 makes contact with the acceptor site 50 .…”

Section: Discussionmentioning

confidence: 99%

Genetic Analysis of Human RNA Binding Motif Protein 48 (RBM48) Reveals an Essential Role in U12-Type Intron Splicing

Siebert

Corll

Gronevelt

et al. 2020

Preprint

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U12-type (minor) introns are found in most multicellular eukaryotes, and constitute ~0.5% of all introns in species with a minor spliceosome required for their splicing. However, the biological relevance of U12-type introns is not well understood. It is known that mutations resulting in aberrant U12-type intron splicing cause developmental defects in both plants and animals. We recently reported that maize RNA Binding Motif Protein 48 (RBM48) is an essential splicing factor for U12-type introns. Maize rbm48 mutants display aberrant genome-wide U12-type intron splicing. This leads to severe defects in endosperm development, resulting in non-viable seeds. In this report, we use CRISPR/Cas9-mediated ablation of RBM48 in human K-562 cells to establish the evolutionary conservation of RBM48 dependent U12-type intron splicing between maize and humans. Comparative RNA-seq analysis performed on RBM48 deficient human cell lines and maize endosperm defined a subset of orthologous minor U12-type containing genes (MIGs) displaying aberrant splicing of U12-type introns in both species. Mutations in the majority of these MIGs have been reported to cause developmental defects in both plants and animals. Thus, a comparison of RNA-seq data between distantly related species containing mutations in RBM48 identifies candidate genes likely to mediate mutant phenotypes of U12-type splicing defects. Our results elucidate deeply conserved post-transcriptional processing mechanisms that are required for normal growth and development of eukaryotes with a minor spliceosome.

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“…This ion and its dynamics have now been successfully identified in the major and minor spliceosomes. 16 , 17 …”

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confidence: 99%

Finding the Ion in the RNA-Stack: Can Computational Models Accurately Predict Key Functional Elements in Large Macromolecular Complexes?

Marcia

Manigrasso

Vivo

2021

J. Chem. Inf. Model.

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This viewpoint discusses the predictive power and impact of computational analyses and simulations to gain prospective, experimentally supported mechanistic insights into complex biological systems. Remarkably, two newly resolved cryoEM structures have confirmed the previous, and independent, prediction of the precise localization and dynamics of key catalytic ions in megadalton-large spliceosomal complexes. This outstanding outcome endorses a prominent synergy of computational and experimental methods in the prospective exploration of such large multicomponent biosystems.

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Structure of the activated human minor spliceosome

Cited by 58 publications

References 77 publications

Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Genetic Analysis of Human RNA Binding Motif Protein 48 (RBM48) Reveals an Essential Role in U12-Type Intron Splicing

Finding the Ion in the RNA-Stack: Can Computational Models Accurately Predict Key Functional Elements in Large Macromolecular Complexes?

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