Advanced ICT Research Institute Kobe, National Institute of Information and Communications Technology, Kobe, Japan; Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
Alfonso G Fernandez
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States
David Finkelstein
Department of Bioinformatics, St. Jude Children’s Research Hospital, Memphis, United States
Margaret Campbell
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States
Satish Kallappagoudar
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States
Carolyn M Jablonowski
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, United States
Andrew J Andrews
Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States
Advanced ICT Research Institute Kobe, National Institute of Information and Communications Technology, Kobe, Japan; Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
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.
