Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Bas de Wolf; Ali Oghabian; Maureen V Akinyi; Sandra Hanks; Eelco C Tromer; Jolien J E van Hooff; Lisa van Voorthuijsen; Laura E van Rooijen; Jens Verbeeren; Esther C H Uijttewaal; Marijke P A Baltissen; Shawn Yost; Philippe Piloquet; Michiel Vermeulen; Berend Snel; Bertrand Isidor; Nazneen Rahman; Mikko J Frilander; Geert J P L Kops

doi:10.15252/embj.2020106536

Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Bas de Wolf, Ali Oghabian, Maureen V Akinyi, Sandra Hanks, Eelco C Tromer, Jolien J E van Hooff, Lisa van Voorthuijsen, Laura E van Rooijen, Jens Verbeeren, Esther C H Uijttewaal, Marijke P A Baltissen, Shawn Yost, Philippe Piloquet, Michiel Vermeulen, Berend Snel, Bertrand Isidor, Nazneen Rahman, Mikko J Frilander, Geert J P L Kops

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

22 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	e106536
Tijdschrift	EMBO Journal
Volume	40
Nummer van het tijdschrift	14
DOI's	https://doi.org/10.15252/embj.2020106536
Status	Gepubliceerd - 15 jul. 2021

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de Wolf, B., Oghabian, A., Akinyi, M. V., Hanks, S., Tromer, E. C., van Hooff, J. J. E., van Voorthuijsen, L., van Rooijen, L. E., Verbeeren, J., Uijttewaal, E. C. H., Baltissen, M. P. A., Yost, S., Piloquet, P., Vermeulen, M., Snel, B., Isidor, B., Rahman, N., Frilander, M. J., & Kops, G. J. P. L. (2021). Chromosomal instability by mutations in the novel minor spliceosome component CENATAC. EMBO Journal, 40(14), e106536. https://doi.org/10.15252/embj.2020106536

@article{8d33c0c3262e4a33a3e18597438fb229,

title = "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.",

keywords = "Amino Acid Sequence, Cell Cycle/genetics, Cell Line, Cell Line, Tumor, Chromosomal Instability/genetics, Chromosomes/genetics, HeLa Cells, Humans, Introns/genetics, Mutation/genetics, Spliceosomes/genetics",

author = "{de Wolf}, Bas and Ali Oghabian and Akinyi, {Maureen V} and Sandra Hanks and Tromer, {Eelco C} and {van Hooff}, {Jolien J E} and {van Voorthuijsen}, Lisa and {van Rooijen}, {Laura E} and Jens Verbeeren and Uijttewaal, {Esther C H} and Baltissen, {Marijke P A} and Shawn Yost and Philippe Piloquet and Michiel Vermeulen and Berend Snel and Bertrand Isidor and Nazneen Rahman and Frilander, {Mikko J} and Kops, {Geert J P L}",

note = "{\textcopyright} 2021 The Authors. Published under the terms of the CC BY 4.0 license.",

year = "2021",

month = jul,

day = "15",

doi = "10.15252/embj.2020106536",

language = "English",

volume = "40",

pages = "e106536",

journal = "EMBO Journal",

issn = "0261-4189",

publisher = "Nature Publishing Group",

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de Wolf, B, Oghabian, A, Akinyi, MV, Hanks, S, Tromer, EC, van Hooff, JJE, van Voorthuijsen, L, van Rooijen, LE, Verbeeren, J, Uijttewaal, ECH, Baltissen, MPA, Yost, S, Piloquet, P, Vermeulen, M, Snel, B, Isidor, B, Rahman, N, Frilander, MJ & Kops, GJPL 2021, 'Chromosomal instability by mutations in the novel minor spliceosome component CENATAC', EMBO Journal, vol. 40, nr. 14, blz. e106536. https://doi.org/10.15252/embj.2020106536

TY - JOUR

T1 - Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

AU - de Wolf, Bas

AU - Oghabian, Ali

AU - Akinyi, Maureen V

AU - Hanks, Sandra

AU - Tromer, Eelco C

AU - van Hooff, Jolien J E

AU - van Voorthuijsen, Lisa

AU - van Rooijen, Laura E

AU - Verbeeren, Jens

AU - Uijttewaal, Esther C H

AU - Baltissen, Marijke P A

AU - Yost, Shawn

AU - Piloquet, Philippe

AU - Vermeulen, Michiel

AU - Snel, Berend

AU - Isidor, Bertrand

AU - Rahman, Nazneen

AU - Frilander, Mikko J

AU - Kops, Geert J P L

PY - 2021/7/15

Y1 - 2021/7/15

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Cell Cycle/genetics

KW - Cell Line

KW - Cell Line, Tumor

KW - Chromosomal Instability/genetics

KW - Chromosomes/genetics

KW - HeLa Cells

KW - Humans

KW - Introns/genetics

KW - Mutation/genetics

KW - Spliceosomes/genetics

U2 - 10.15252/embj.2020106536

DO - 10.15252/embj.2020106536

M3 - Article

C2 - 34009673

SN - 0261-4189

VL - 40

SP - e106536

JO - EMBO Journal

JF - EMBO Journal

IS - 14

ER -

Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

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