Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail
- St Jude Children's Research Hospital, United States
- Fox Chase Cancer Center, United States
- National Institute of Information and Communications Technology, Japan
- Osaka University, Japan
Abstract
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 (Yadav et al., 2017). 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, hydroxyurea and influencing DNA repair. In cancer, only one of thirty alleles encoding H3 is mutated. Whilst co-expression of wild-type H3 rescues most G34 mutant phenotypes, G34R causes dominant hydroxyurea sensitivity and 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.
Data availability
RNAseq data have been deposited in GEO under accession code GSE162572.
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Surprising Phenotypic Diversity of Cancer-associated mutations at Gly 34 in the Histone H3 tailNCBI Gene Expression Omnibus, GSE162572.
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S. pombe acetyltransferase mutants identifies redundant pathways of gene regulation, dual-channel datasetNCBI Gene Expression Omnibus, GSE17259.
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S. pombe acetyltransferase mutants identifies redundant pathways of gene regulation, Affymetrix datasetNCBI Gene Expression Omnibus, GSE17262.
Article and author information
Author details
Funding
St. Baldrick's Foundation (Research grant with generous support from the Henry Cermak fund for Pediatric Cancer Research.)
- Janet F Partridge
National Cancer Institute (Cancer Center support grant (NCI CCSG 2 P30 CA21765))
- Rajesh K Yadav
- Janet F Partridge
American Lebanese Syrian Associated Charities
- Brandon R Lowe
- Rajesh K Yadav
- Patrick Schreiner
- Alfonso G Fernandez
- David Finkelstein
- Margaret Campbell
- Satish Kallappagoudar
- Carolyn M Jablonowski
- Janet F Partridge
National Institutes of Health (NIH GM102503)
- Andrew J Andrews
Fox Chase Cancer Center (Board of Associates Fellowship)
- Ryan A Henry
Japan Society for the Promotion of Science (Kakheni grant JP19H03202 and JP20H05894)
- Atsushi Matsuda
Japan Society for the Promotion of Science (Kakheni grants JP18H05533 and JP20H00454)
- Yasushi Hiraoka
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jerry L Workman, Stowers Institute for Medical Research, United States
Version history
- Received: December 2, 2020
- Accepted: January 30, 2021
- Accepted Manuscript published: February 1, 2021 (version 1)
- Version of Record published: February 9, 2021 (version 2)
Copyright
© 2021, Lowe et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail
eLife 10:e65369.
https://doi.org/10.7554/eLife.65369
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