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Yadav RK , Jablonowski CM , Fernandez AG , Lowe BR , Henry RA , Finkelstein D , Barnum KJ , Pidoux AL , Kuo YM , Huang J , O'Connell MJ , Andrews AJ , Onar-Thomas A , Allshire RC , Partridge JF
Histone H3G34R mutation causes replication stress, homologous recombination defects and genomic instability in S. pombe
Elife. 2017 Jul 18;6
PMID: 28718400    PMCID: PMC5515577   
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Recurrent somatic mutations of H3F3A 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 set2 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.
2050-084x 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 ORCID: http://orcid.org/0000-0003-1102-6305 Journal Article England Elife. 2017 Jul 18;6. doi: 10.7554/eLife.27406.