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Paediatric Glioma Histone H3.3 K27M/G34R Mutations Drive Abnormalities in Phase-Separated PML Nuclear Bodies.

ABSTRACT: Paediatric Glioma Histone H3.3 K27M/G34R Mutations Drive Abnormalities in Phase-Separated PML Nuclear Bodies.

PROVIDER: PRJNA864751 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20729100.fastq.gz	Fastqsanger.gz
	SRR20729101.fastq.gz	Fastqsanger.gz
	SRR20729102.fastq.gz	Fastqsanger.gz
	SRR20729103.fastq.gz	Fastqsanger.gz
	SRR20729104.fastq.gz	Fastqsanger.gz

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Paediatric Glioma Histone H3.3 K27M/G34R Mutations Drive Abnormalities in Phase-Separated PML Nuclear Bodies.

Project description:Point mutations in histone variant H3.3 (H3.3 K27M, H3.3 G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in paediatric gliomas. It is clear that H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are an area of active investigation. Histone H3.3 has been previously linked to PML, a gene which is frequently mutated in Acute Promyelocytic Leukaemia. We find that H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to PML-mutated Acute Promyelocytic Leukaemias, H3.3-mutated patient-derived gliomas cells are also sensitive to drugs which target PML bodies. We identify PML as a contributor to oncogenesis in H3.3-mutated gliomas and our results indicate that PML-targeting strategies may prove effective at treating H3.3-mutated paediatric gliomas.

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Project description:Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R mutant histone H3.3. H3.3-G34R mutants are common in tumors additionally mutant for p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, but minimally affects transcriptional control. H3-G34R mutants exhibit genomic instability and increased replicative stress including slowed replication fork restart although DNA replication checkpoints are functional. H3-G34R mutants are defective for DNA damage repair by homologous recombination (HR), and on damage have altered HR protein dynamics suggestive that H3-G34R slows resolution of HR-mediated repair. In summary our analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma.

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