Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail.
Elife
; 102021 02 01.
Article
em En
| MEDLINE
| ID: mdl-33522486
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Schizosaccharomyces
/
Histonas
/
Proteínas Mutantes
/
Recombinação Homóloga
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Revista:
Elife
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos