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.
Funder
Dutch Research Council
De Cock-Hadders foundation
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
LPDP
Fördergemeinschaft Kinderkrebs-Zentrum Hamburg
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
H2020 European Research Council
KWF Kankerbestrijding
Stichting Kinderoncologie Groningen
Rijksuniversiteit Groningen
Publisher
Public Library of Science (PLoS)
Subject
Cancer Research,Genetics(clinical),Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics
Cited by
13 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献