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Histone H3-G34V and H3-G34R mutant fission yeast exhibit distinct chromatin changes and different DNA damage sensitivities.

ABSTRACT: 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.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE106979 | GEO | 2018/11/15

REPOSITORIES: GEO

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Histone H3G34R mutation causes replicative stress, defective homologous recombination and genomic instability in Fission Yeast

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