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Lowe BR , Yadav RK , Henry RA , Schreiner P , Matsuda A , Fernandez AG , Finkelstein D , Campbell M , Kallappagoudar S , Jablonowski CM , Andrews AJ , Hiraoka Y , Partridge JF
Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail
Elife. 2021 Feb 1;10
PMID: 33522486    PMCID: PMC7872514   
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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. 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, and hydroxyurea; and influencing DNA repair. In cancer, only 1 of 30 alleles encoding H3 is mutated. Whilst co-expression of wild-type H3 rescues most G34 mutant phenotypes, G34R causes dominant hydroxyurea sensitivity, 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.
Notes
2050-084x Lowe, Brandon R Yadav, Rajesh K Henry, Ryan A Schreiner, Patrick Orcid: 0000-0001-5391-2642 Matsuda, Atsushi Orcid: 0000-0003-0510-213x Fernandez, Alfonso G Finkelstein, David Campbell, Margaret Kallappagoudar, Satish Jablonowski, Carolyn M Andrews, Andrew J Hiraoka, Yasushi Orcid: 0000-0001-9407-8228 Partridge, Janet F Orcid: 0000-0003-1102-6305 Research grant with generous support from the Henry Cermak fund for Pediatric Cancer Research./St. Baldrick's Foundation/ Cancer Center support grant (NCI CCSG 2 P30 CA21765)/CA/NCI NIH HHS/United States NIH GM102503/NH/NIH HHS/United States Board of Associates Fellowship/Fox Chase Cancer Center/ Kakheni grant JP19H03202 and JP20H05894/Japan Society for the Promotion of Science/ Kakheni grants JP18H05533 and JP20H00454/Japan Society for the Promotion of Science/ Research grant with generous support from the Henry Cermak fund for Pediatric Cancer Research/St. Baldrick's Foundation/ Kakheni grant JP19H03202/Japan Society for the Promotion of Science/ Kakheni grants JP18H05533/Japan Society for the Promotion of Science/ JP20H05894/Japan Society for the Promotion of Science/ JP20H00454/Japan Society for the Promotion of Science/ Journal Article Elife. 2021 Feb 1;10:e65369. doi: 10.7554/eLife.65369.