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

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 alterat...

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Autores principales: Irena Bočkaj, Tosca E I Martini, Eduardo S de Camargo Magalhães, Petra L Bakker, Tiny G J Meeuwsen-de Boer, Inna Armandari, Saskia L Meuleman, Marin T Mondria, Colin Stok, Yannick P Kok, Bjorn Bakker, René Wardenaar, Jonas Seiler, Mathilde J C Broekhuis, Hilda van den Bos, Diana C J Spierings, Femke C A Ringnalda, Hans Clevers, Ulrich Schüller, Marcel A T M van Vugt, Floris Foijer, Sophia W M Bruggeman
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Publicado: Public Library of Science (PLoS) 2021
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spelling oai:doaj.org-article:e3b40f56962c48b392b15bc0a11a6d552021-12-02T20:03:15ZThe H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma.1553-73901553-740410.1371/journal.pgen.1009868https://doaj.org/article/e3b40f56962c48b392b15bc0a11a6d552021-11-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009868https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404While 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.Irena BočkajTosca E I MartiniEduardo S de Camargo MagalhãesPetra L BakkerTiny G J Meeuwsen-de BoerInna ArmandariSaskia L MeulemanMarin T MondriaColin StokYannick P KokBjorn BakkerRené WardenaarJonas SeilerMathilde J C BroekhuisHilda van den BosDiana C J SpieringsFemke C A RingnaldaHans CleversUlrich SchüllerMarcel A T M van VugtFloris FoijerSophia W M BruggemanPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 11, p e1009868 (2021)
institution DOAJ
collection DOAJ
language EN
topic Genetics
QH426-470
spellingShingle Genetics
QH426-470
Irena Bočkaj
Tosca E I Martini
Eduardo S de Camargo Magalhães
Petra L Bakker
Tiny G J Meeuwsen-de Boer
Inna Armandari
Saskia L Meuleman
Marin T Mondria
Colin Stok
Yannick P Kok
Bjorn Bakker
René Wardenaar
Jonas Seiler
Mathilde J C Broekhuis
Hilda van den Bos
Diana C J Spierings
Femke C A Ringnalda
Hans Clevers
Ulrich Schüller
Marcel A T M van Vugt
Floris Foijer
Sophia W M Bruggeman
The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma.
description 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.
format article
author Irena Bočkaj
Tosca E I Martini
Eduardo S de Camargo Magalhães
Petra L Bakker
Tiny G J Meeuwsen-de Boer
Inna Armandari
Saskia L Meuleman
Marin T Mondria
Colin Stok
Yannick P Kok
Bjorn Bakker
René Wardenaar
Jonas Seiler
Mathilde J C Broekhuis
Hilda van den Bos
Diana C J Spierings
Femke C A Ringnalda
Hans Clevers
Ulrich Schüller
Marcel A T M van Vugt
Floris Foijer
Sophia W M Bruggeman
author_facet Irena Bočkaj
Tosca E I Martini
Eduardo S de Camargo Magalhães
Petra L Bakker
Tiny G J Meeuwsen-de Boer
Inna Armandari
Saskia L Meuleman
Marin T Mondria
Colin Stok
Yannick P Kok
Bjorn Bakker
René Wardenaar
Jonas Seiler
Mathilde J C Broekhuis
Hilda van den Bos
Diana C J Spierings
Femke C A Ringnalda
Hans Clevers
Ulrich Schüller
Marcel A T M van Vugt
Floris Foijer
Sophia W M Bruggeman
author_sort Irena Bočkaj
title The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma.
title_short The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma.
title_full The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma.
title_fullStr The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma.
title_full_unstemmed The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma.
title_sort h3.3k27m oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma.
publisher Public Library of Science (PLoS)
publishDate 2021
url https://doaj.org/article/e3b40f56962c48b392b15bc0a11a6d55
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