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Elife. 2017 Jul 18;6. pii: e27406. doi: 10.7554/eLife.27406.

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

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Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States.
Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.
Department of Bioinformatics, St. Jude Children's Research Hospital, Memphis, United States.
Department of Oncological Sciences and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.
Wellcome Trust School for Biological Sciences, University of Edinburgh, Edinburgh, Scotland.
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, United States.


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.


H3K36; S. pombe; cancer; chromatin; chromosomes; genes; homologous recombination

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