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Surprising Phenotypic Diversity of Cancer-associated mutations at Gly 34 in the Histone H3 tail

ABSTRACT: Deep sequencing of cancer genomes has identified frequent mutation of core histones, termed oncohistones, but the role of some mutants is poorly understood. Here, using fission yeast as a model, we determine the consequences of mutation of histone H3.3 at Gly 34, a site frequently mutated in pediatric cortical high-grade glioma (G34R/V), and in virtually all giant cell tumors of bone (G34W). H3-G34 mutations cause a surprising diversity of outcomes, differentially affecting modification of the nearby H3K36 residue, subtelomeric silencing, genomic stability, sensitivity to irradiation, alkylating agents, hydroxyurea and influencing DNA repair. Since fifteen genes encode H3 isoforms, and only one allele is targeted in cancer, G34R/V/W H3 likely represents a small portion of total cellular H3. Whilst the presence of wild type H3 rescues most G34 mutant phenotypes, hydroxyurea sensitivity, subtelomeric silencing and homologous recombination defects dominate in cells expressing G34R and wild type H3. Together, these studies demonstrate the complexity associated with different substitutions at even a single residue in histone H3 and highlight the utility of genetically tractable systems for their analysis.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE162572 | GEO | 2021/02/08

REPOSITORIES: GEO

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

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Surprising Phenotypic Diversity of Cancer-associated mutations at Gly 34 in the Histone H3 tail

Project description:Surprising Phenotypic Diversity of Cancer-associated mutations at Gly 34 in the Histone H3 tail

| PRJNA682226 | ENA

Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail.

Project description:Sequencing of cancer genomes has identified recurrent somatic mutations in histones, termed oncohistones, which are frequently poorly understood. Previously we showed that fission yeast expressing only the H3.3G34R mutant identified in aggressive pediatric glioma had reduced H3K36 trimethylation and acetylation, increased genomic instability and replicative stress, and defective homology-dependent DNA damage repair. Here we show that surprisingly distinct phenotypes result from G34V (also in glioma) and G34W (giant cell tumors of bone) mutations, differentially affecting H3K36 modifications, subtelomeric silencing, genomic stability; sensitivity to irradiation, alkylating agents, and hydroxyurea; and influencing DNA repair. In cancer, only 1 of 30 alleles encoding H3 is mutated. Whilst co-expression of wild-type H3 rescues most G34 mutant phenotypes, G34R causes dominant hydroxyurea sensitivity, homologous recombination defects, and dominant subtelomeric silencing. Together, these studies demonstrate the complexity associated with different substitutions at even a single residue in H3 and highlight the utility of genetically tractable systems for their analysis.

| S-EPMC7872514 | biostudies-literature

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