Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail.
Brandon R LoweRajesh K YadavRyan A HenryPatrick A SchreinerAtsushi MatsudaAlfonso G FernandezDavid FinkelsteinMargaret CampbellSatish KallappagoudarCarolyn M JablonowskiAndrew J AndrewsYasushi HiraokaJanet F PartridgePublished in: eLife (2021)
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.
Keyphrases
- dna repair
- wild type
- dna damage
- papillary thyroid
- giant cell
- copy number
- dna damage response
- squamous cell
- oxidative stress
- poor prognosis
- sickle cell disease
- mouse model
- childhood cancer
- bone mineral density
- dna methylation
- body composition
- case control
- radiation induced
- histone deacetylase
- postmenopausal women
- binding protein