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The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma

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The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma. / Bočkaj, Irena; Martini, Tosca E I; de Camargo Magalhães, Eduardo S; Bakker, Petra L; Meeuwsen-de Boer, Tiny G J; Armandari, Inna; Meuleman, Saskia L; Mondria, Marin T; Stok, Colin; Kok, Yannick P; Bakker, Bjorn; Wardenaar, René; Seiler, Jonas; Broekhuis, Mathilde J C; van den Bos, Hilda; Spierings, Diana C J; Ringnalda, Femke C A; Clevers, Hans; Schüller, Ulrich; van Vugt, Marcel A T M; Foijer, Floris; Bruggeman, Sophia W M.

in: PLOS GENET, Jahrgang 17, Nr. 11, e1009868, 11.2021.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Bočkaj, I, Martini, TEI, de Camargo Magalhães, ES, Bakker, PL, Meeuwsen-de Boer, TGJ, Armandari, I, Meuleman, SL, Mondria, MT, Stok, C, Kok, YP, Bakker, B, Wardenaar, R, Seiler, J, Broekhuis, MJC, van den Bos, H, Spierings, DCJ, Ringnalda, FCA, Clevers, H, Schüller, U, van Vugt, MATM, Foijer, F & Bruggeman, SWM 2021, 'The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma', PLOS GENET, Jg. 17, Nr. 11, e1009868. https://doi.org/10.1371/journal.pgen.1009868

APA

Bočkaj, I., Martini, T. E. I., de Camargo Magalhães, E. S., Bakker, P. L., Meeuwsen-de Boer, T. G. J., Armandari, I., Meuleman, S. L., Mondria, M. T., Stok, C., Kok, Y. P., Bakker, B., Wardenaar, R., Seiler, J., Broekhuis, M. J. C., van den Bos, H., Spierings, D. C. J., Ringnalda, F. C. A., Clevers, H., Schüller, U., ... Bruggeman, S. W. M. (2021). The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma. PLOS GENET, 17(11), [e1009868]. https://doi.org/10.1371/journal.pgen.1009868

Vancouver

Bočkaj I, Martini TEI, de Camargo Magalhães ES, Bakker PL, Meeuwsen-de Boer TGJ, Armandari I et al. The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma. PLOS GENET. 2021 Nov;17(11). e1009868. https://doi.org/10.1371/journal.pgen.1009868

Bibtex

@article{a5a2f5fd89c44aa7a0f626f12817ae6b,
title = "The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma",
abstract = "While comprehensive molecular profiling of histone H3.3 mutant pediatric high-grade glioma has revealed extensive dysregulation of the chromatin landscape, the exact mechanisms driving tumor formation remain poorly understood. Since H3.3 mutant gliomas also exhibit high levels of copy number alterations, we set out to address if the H3.3K27M oncohistone leads to destabilization of the genome. Hereto, we established a cell culture model allowing inducible H3.3K27M expression and observed an increase in mitotic abnormalities. We also found enhanced interaction of DNA replication factors with H3.3K27M during mitosis, indicating replication defects. Further functional analyses revealed increased genomic instability upon replication stress, as represented by mitotic bulky and ultrafine DNA bridges. This co-occurred with suboptimal 53BP1 nuclear body formation after mitosis in vitro, and in human glioma. Finally, we observed a decrease in ultrafine DNA bridges following deletion of the K27M mutant H3F3A allele in primary high-grade glioma cells. Together, our data uncover a role for H3.3 in DNA replication under stress conditions that is altered by the K27M mutation, promoting genomic instability and potentially glioma development.",
keywords = "Brain Neoplasms/genetics, Child, DNA Replication/genetics, Gene Expression Regulation, Neoplastic, Genomic Instability, Glioma/genetics, Histones/physiology, Humans, Mitosis/genetics",
author = "Irena Bo{\v c}kaj and Martini, {Tosca E I} and {de Camargo Magalh{\~a}es}, {Eduardo S} and Bakker, {Petra L} and {Meeuwsen-de Boer}, {Tiny G J} and Inna Armandari and Meuleman, {Saskia L} and Mondria, {Marin T} and Colin Stok and Kok, {Yannick P} and Bjorn Bakker and Ren{\'e} Wardenaar and Jonas Seiler and Broekhuis, {Mathilde J C} and {van den Bos}, Hilda and Spierings, {Diana C J} and Ringnalda, {Femke C A} and Hans Clevers and Ulrich Sch{\"u}ller and {van Vugt}, {Marcel A T M} and Floris Foijer and Bruggeman, {Sophia W M}",
year = "2021",
month = nov,
doi = "10.1371/journal.pgen.1009868",
language = "English",
volume = "17",
journal = "PLOS GENET",
issn = "1553-7404",
publisher = "Public Library of Science",
number = "11",

}

RIS

TY - JOUR

T1 - The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma

AU - Bočkaj, Irena

AU - Martini, Tosca E I

AU - de Camargo Magalhães, Eduardo S

AU - Bakker, Petra L

AU - Meeuwsen-de Boer, Tiny G J

AU - Armandari, Inna

AU - Meuleman, Saskia L

AU - Mondria, Marin T

AU - Stok, Colin

AU - Kok, Yannick P

AU - Bakker, Bjorn

AU - Wardenaar, René

AU - Seiler, Jonas

AU - Broekhuis, Mathilde J C

AU - van den Bos, Hilda

AU - Spierings, Diana C J

AU - Ringnalda, Femke C A

AU - Clevers, Hans

AU - Schüller, Ulrich

AU - van Vugt, Marcel A T M

AU - Foijer, Floris

AU - Bruggeman, Sophia W M

PY - 2021/11

Y1 - 2021/11

N2 - While comprehensive molecular profiling of histone H3.3 mutant pediatric high-grade glioma has revealed extensive dysregulation of the chromatin landscape, the exact mechanisms driving tumor formation remain poorly understood. Since H3.3 mutant gliomas also exhibit high levels of copy number alterations, we set out to address if the H3.3K27M oncohistone leads to destabilization of the genome. Hereto, we established a cell culture model allowing inducible H3.3K27M expression and observed an increase in mitotic abnormalities. We also found enhanced interaction of DNA replication factors with H3.3K27M during mitosis, indicating replication defects. Further functional analyses revealed increased genomic instability upon replication stress, as represented by mitotic bulky and ultrafine DNA bridges. This co-occurred with suboptimal 53BP1 nuclear body formation after mitosis in vitro, and in human glioma. Finally, we observed a decrease in ultrafine DNA bridges following deletion of the K27M mutant H3F3A allele in primary high-grade glioma cells. Together, our data uncover a role for H3.3 in DNA replication under stress conditions that is altered by the K27M mutation, promoting genomic instability and potentially glioma development.

AB - While comprehensive molecular profiling of histone H3.3 mutant pediatric high-grade glioma has revealed extensive dysregulation of the chromatin landscape, the exact mechanisms driving tumor formation remain poorly understood. Since H3.3 mutant gliomas also exhibit high levels of copy number alterations, we set out to address if the H3.3K27M oncohistone leads to destabilization of the genome. Hereto, we established a cell culture model allowing inducible H3.3K27M expression and observed an increase in mitotic abnormalities. We also found enhanced interaction of DNA replication factors with H3.3K27M during mitosis, indicating replication defects. Further functional analyses revealed increased genomic instability upon replication stress, as represented by mitotic bulky and ultrafine DNA bridges. This co-occurred with suboptimal 53BP1 nuclear body formation after mitosis in vitro, and in human glioma. Finally, we observed a decrease in ultrafine DNA bridges following deletion of the K27M mutant H3F3A allele in primary high-grade glioma cells. Together, our data uncover a role for H3.3 in DNA replication under stress conditions that is altered by the K27M mutation, promoting genomic instability and potentially glioma development.

KW - Brain Neoplasms/genetics

KW - Child

KW - DNA Replication/genetics

KW - Gene Expression Regulation, Neoplastic

KW - Genomic Instability

KW - Glioma/genetics

KW - Histones/physiology

KW - Humans

KW - Mitosis/genetics

U2 - 10.1371/journal.pgen.1009868

DO - 10.1371/journal.pgen.1009868

M3 - SCORING: Journal article

C2 - 34752469

VL - 17

JO - PLOS GENET

JF - PLOS GENET

SN - 1553-7404

IS - 11

M1 - e1009868

ER -