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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.

Author information

1
Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States.
2
Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.
3
Department of Bioinformatics, St. Jude Children's Research Hospital, Memphis, United States.
4
Department of Oncological Sciences and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.
5
Wellcome Trust School for Biological Sciences, University of Edinburgh, Edinburgh, Scotland.
6
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, United States.

Abstract

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.

KEYWORDS:

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

PMID:
28718400
PMCID:
PMC5515577
DOI:
10.7554/eLife.27406
[Indexed for MEDLINE]
Free PMC Article

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