Histone H3G34R mutation causes replication stress, homologous recombination defects and genomic instability in S. pombe

• Published in: eLife Vol. 6
• Main Authors: Yadav, Rajesh K, Jablonowski, Carolyn M, Fernandez, Alfonso G, Lowe, Brandon R, Henry, Ryan A, Finkelstein, David, Barnum, Kevin J, Pidoux, Alison L, Kuo, Yin-Ming, Huang, Jie, O'Connell, Matthew J, Andrews, Andrew J, Onar-Thomas, Arzu, Allshire, Robin C, Partridge, Janet F
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 18.07.2017; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Acetylation; Ascomycota; Brain tumors; Cancer; Chromatin; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA methylation; DNA Repair; DNA Replication; Enzymes; Experiments; Gene mutation; Genes; Genes and Chromosomes; Genetic aspects; Genetic recombination; Genetic research; Genomic Instability; Glioma; H3K36; Histone H3; Histones; Histones - genetics; Histones - metabolism; Homologous Recombination; Hospitals; Identification and classification; Intermediates; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Mutation, Missense; p53 Protein; Pediatrics; Properties; Proteins; Replication; Schizosaccharomyces - genetics; Schizosaccharomyces - metabolism; Transcription; Yeast; homologous recombination; S. pombe; genes; chromosomes; cancer; chromatin; H3K36
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.27406

Recurrent somatic mutations of in aggressive pediatric high-grade gliomas generate K27M or G34R/V mutant histone H3.3. H3.3-G34R/V mutants are common in tumors with mutations in 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, and mutants show partial transcriptional overlap with deletions. H3-G34R mutants exhibit genomic instability and increased replication 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 have altered HR protein dynamics in both damaged and untreated cells. These data suggest H3-G34R slows resolution of HR-mediated repair and that unresolved replication intermediates impair chromosome segregation. This analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma.