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

Bockaj, Irena; Martini, Tosca E. I.; Magalhães, Eduardo Sabino de Camargo; Bakker, Petra L.; Boer, Tiny G. J. Meeuwsen–de; Armandari, Inna; Meuleman, Saskia L; Mondria, Marin T; Stok, Colin; Kok, Yannick P; Bakker, Björn; Wardenaar, René; Seiler, Jonas; Broekhuis, Mathilde; Bos, Hilda van den; Spierings, Diana C.J.; Ringnalda, Femke; Schüller, Ulrich; Vugt, Marcel A.T.M. van; Foijer, Floris; Bruggeman, Sophia W.M.

doi:10.1371/journal.pgen.1009868

Cited by 26 publications

(22 citation statements)

References 95 publications

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“…By dissecting how H3.3 mutants skew DNA repair, we show that mutations in core chromatin components induce genome instability by dysregulating the recruitment of repair factors at damaged RF (Figure S4D). Aberrant repair of damaged RF leads to mitotic aberrations (Berti et al, 2020), which were recently reported in cells expressing the H3.3K27M mutant (Bočkaj et al, 2021) and is the likely cause of genome instability. The influence of co-occurring genetic alterations (Mackay et al, 2017) on this phenotype should be evaluated in future studies.…”

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

“…Besides their effect on gene expression, pHGG H3.3 mutations also promote genome instability (Bočkaj et al, 2021; Fang et al, 2018; Haase et al, 2022; Pfister et al, 2014; Schwartzentruber et al, 2012; Sturm et al, 2012; Yadav et al, 2017), which is one of the major drivers of cellular transformation (Hanahan, 2022). In particular, H3.3 mutant pHGGs display increased copy number alterations and chromosomal rearrangements compared to wild-type (WT) H3.3 tumors (Bočkaj et al, 2021; Mackay et al, 2017; Schwartzentruber et al, 2012). Mechanistically, H3 G34 mutations in fission yeast and mammals and the non-pHGG H3.3 K36M mutation in human cells hijack the response to DNA damage (Fang et al, 2016, 2018; Lowe et al, 2021; Pfister et al, 2014; Yadav et al, 2017) by dominantly interfering with the DNA repair-promoting function of WT H3.3 (Juhász et al, 2018; Luijsterburg et al, 2016) or by downregulating DNA damage response genes (Haase et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Aberrant DNA repair is a vulnerability in histone H3.3-mutant brain tumors

Rondinelli

Giacomini

Piquet

et al. 2022

Preprint

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Pediatric high-grade gliomas (pHGG) are devastating and incurable brain tumors with recurrent mutations in histone H3.3. These mutations promote oncogenesis by dysregulating gene expression through alterations of histone modifications. We identify aberrant DNA repair as an independent oncogenic mechanism, which fosters genome instability and tumor cell growth in H3.3 mutant pHGG, thus opening new therapeutic options. The two most frequent H3.3 mutations in pHGG, K27M and G34R, drive aberrant repair of replication-associated damage by non-homologous end joining (NHEJ). Aberrant NHEJ is mediated by the DNA repair enzyme Polynucleotide Kinase 3'-Phosphatase (PNKP), which shows increased association with mutant H3.3 at damaged replication forks. PNKP sustains the proliferation of cells bearing H3.3 mutations, thus conferring a molecular vulnerability, specific to mutant cells, with potential for therapeutic targeting.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aberrant DNA repair is a vulnerability in histone H3.3-mutant brain tumors

Rondinelli

Giacomini

Piquet

et al. 2022

Preprint

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“…Informed consent was given, and local ethics committee approval was granted for use of the patient material. The scWGS and analysis were performed as described previously [ 33 , 56 , 57 ]. Anonymized reads of the medulloblastoma samples are deposited at the European Nucleotide Archive/ENA ( , accessed on 24 July 2022), accession number PRJEB54865.…”

Section: Methodsmentioning

confidence: 99%

Chromosomal Instability Characterizes Pediatric Medulloblastoma but Is Not Tolerated in the Developing Cerebellum

Bockaj

Martini

Smit

et al. 2022

IJMS

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Medulloblastoma is a pediatric brain malignancy that consists of four transcriptional subgroups. Structural and numerical aneuploidy are common in all subgroups, although they are particularly profound in Group 3 and Group 4 medulloblastoma and in a subtype of SHH medulloblastoma termed SHHα. This suggests that chromosomal instability (CIN), the process leading to aneuploidy, is an important player in medulloblastoma pathophysiology. However, it is not known if there is ongoing CIN in medulloblastoma or if CIN affects the developing cerebellum and promotes tumor formation. To investigate this, we performed karyotyping of single medulloblastoma cells and demonstrated the presence of distinct tumor cell clones harboring unique copy number alterations, which is suggestive of ongoing CIN. We also found enrichment for processes related to DNA replication, repair, and mitosis in both SHH medulloblastoma and in the highly proliferative compartment of the presumed tumor cell lineage-of-origin, the latter also being sensitive to genotoxic stress. However, when challenging these tumor cells-of-origin with genetic lesions inducing CIN using transgenic mouse modeling, we found no evidence for large chromosomal aberrations in the cerebellum or for medulloblastoma formation. We therefore conclude that without a background of specific genetic mutations, CIN is not tolerated in the developing cerebellum in vivo and, thus, by itself is not sufficient to initiate medulloblastoma.

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“…In solid tumors, mutant chromatin remodelers differentially recruit histone modifiers that confer chemoresistance (Drosos et al, 2022). These cancer-associated mutant histones are referred to as oncohistones, which are now emerging as a class of prominent biomarkers of cancers (Bočkaj et al, 2021). In this review, we address the molecular and mechanistic underpinnings of nuclear envelope factors, their crosstalk with chromatin, and their pivotal role in cancer initiation and progression.…”

Section: Introductionmentioning

confidence: 99%

Nuclear envelope, chromatin organizers, histones, and DNA: The many achilles heels exploited across cancers

Balaji

Saha

Deshpande

et al. 2022

Front. Cell Dev. Biol.

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In eukaryotic cells, the genome is organized in the form of chromatin composed of DNA and histones that organize and regulate gene expression. The dysregulation of chromatin remodeling, including the aberrant incorporation of histone variants and their consequent post-translational modifications, is prevalent across cancers. Additionally, nuclear envelope proteins are often deregulated in cancers, which impacts the 3D organization of the genome. Altered nuclear morphology, genome organization, and gene expression are defining features of cancers. With advances in single-cell sequencing, imaging technologies, and high-end data mining approaches, we are now at the forefront of designing appropriate small molecules to selectively inhibit the growth and proliferation of cancer cells in a genome- and epigenome-specific manner. Here, we review recent advances and the emerging significance of aberrations in nuclear envelope proteins, histone variants, and oncohistones in deregulating chromatin organization and gene expression in oncogenesis.

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

Cited by 26 publications

References 95 publications

Aberrant DNA repair is a vulnerability in histone H3.3-mutant brain tumors

Aberrant DNA repair is a vulnerability in histone H3.3-mutant brain tumors

Chromosomal Instability Characterizes Pediatric Medulloblastoma but Is Not Tolerated in the Developing Cerebellum

Nuclear envelope, chromatin organizers, histones, and DNA: The many achilles heels exploited across cancers

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