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Chromosomal instability by mutations in the novel minor spliceosome component CENATAC.

ABSTRACT: 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.

SUBMITTER: de Wolf B

PROVIDER: S-EPMC8280824 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Chromosomal instability by mutations in the novel minor spliceosome component CENATAC.

de Wolf Bas B Oghabian Ali A Akinyi Maureen V MV Hanks Sandra S Tromer Eelco C EC van Hooff Jolien J E JJE van Voorthuijsen Lisa L van Rooijen Laura E LE Verbeeren Jens J Uijttewaal Esther C H ECH Baltissen Marijke P A MPA Yost Shawn S Piloquet Philippe P Vermeulen Michiel M Snel Berend B Isidor Bertrand B Rahman Nazneen N Frilander Mikko J MJ Kops Geert J P L GJPL

The EMBO journal 20210519 14

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 ...[more]

PMID: 34009673

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Project description:U12-type introns were originally recognized based on their highly conserved non-consensus AT-AC termini1,2, which are spliced by a separate minor spliceosome3,4. Padgett and Krainer groups later showed that terminal dinucleotides do not differentiate U12-type from U2-type introns, as there are U12-type introns with GT-AG termini and U2-type introns with AT-AC termini5,6. Rather, U12-type introns are recognized by their divergent and highly conserved 5’ splice site (5’ss) and branch point sequences, which both differ from the consensus sequences found in U2-type introns. To date, no functional differences have been ascribed to AT-AC or GT-AG subtypes of U12-type introns, nor have RNAseq analyses of minor spliceosome diseases reported any subtype specificity. Here, we describe a novel protein component of the minor spliceosome, encoded by the CENATAC locus, that is required for accurate splicing of AT-AC but not GT-AG type minor introns. CENATAC was initially identified in a subset of Mosaic Variegated Aneuploidy (MVA) patients with mutations in CENATAC, which lead to chromosome congression defects during mitosis. Earlier large-scale proteomic analyses tentatively classified CENATAC as a spliceosome component and phylogenetic analyses showed co-segregation of CENATAC with minor spliceosome components. Targeted depletion of CENATAC in HeLa cells, followed by RNAseq revealed global retention of AT-AC minor subtype introns with more than 60% showing statistically significant (up to 90%) intron retention (IR). Additionally, U12-type introns with 5’-AT, but divergent 3’-terminal dinucleotides also showed significant IR. We also detected cryptic U2-type splice site activation near affected AT-AC introns. In contrast, about 10% of GT-AG subtype introns responded to CENATAC depletion. Co-IP experiments revealed that CENATAC is not a U11/U12 di-snRNP component as expected for a specificity factor, but rather associates with the U4atac/U6atac.U5 tri-snRNP via interaction with PRPF3/4, suggesting a role for minor tri-snRNP in initial 5’ss recognition. CENATAC also interacts with TXNL4B, a paralog of TXNL4A in the major tri-snRNP. Finally, several genes encoding chromosome congression factors harbor U12 AT-AC-type introns that were highly retained in CENATAC depleted cells, potentially explaining the aneuploidy phenotype observed in MVA patients.

Project description:Most solid cancers are characterized by chromosomal instability (CIN)-an elevated rate of large-scale chromosomal aberrations and ploidy changes. Chromosomal instability may arise through mutations in a range of genomic integrity loci and is commonly associated with fast disease progression, poor prognosis, and multidrug resistance. However, the evolutionary forces promoting CIN-inducing alleles (hereafter, CIN mutators) during carcinogenesis remain poorly understood. Here, we develop a stochastic, individual-based model of indirect selection experienced by CIN mutators via genomic associations with fitness-affecting mutations. Because mutations associated with CIN affect large swaths of the genome and have the potential to simultaneously comprise many individual loci, we show that indirect selection on CIN mutators is critically influenced by genome organization. In particular, we find strong support for a key role played by the spatial clustering of loci with either beneficial or deleterious mutational effects. Genomic clustering of selected loci allows CIN mutators to generate favorable chromosomal changes that facilitate their rapid expansion within a neoplasm and, in turn, accelerate carcinogenesis. We then examine the distribution of oncogenic and tumor-suppressing loci in the human genome and find both to be potentially more clustered along the chromosome than expected, leading us to speculate that human genome may be susceptible to CIN hitchhiking. More quantitative data on fitness effects of individual mutations will be necessary, though, to assess the true levels of clustering in the human genome and the effectiveness of indirect selection for CIN. Finally, we use our model to examine how therapeutic strategies that increase the deleterious burden of genetically unstable cells by raising either the rate of CIN or the cost of deleterious mutations affect CIN evolution. We find that both can inhibit CIN hitchhiking and delay carcinogenesis in some circumstances, yet, in line with earlier work, we find the latter to be considerably more effective.

Dataset Information

Chromosomal instability by mutations in the novel minor spliceosome component CENATAC.

Publications

Chromosomal instability by mutations in the novel minor spliceosome component CENATAC.

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