Surprising Phenotypic Diversity of Cancer-associated Mutations of Gly 34 in the Histone H3 Tail

Overview

Journal Elife

Specialty Biology

Date 2021 Feb 1

PMID 33522486

Citations 17

Authors

Brandon R Lowe

Rajesh K Yadav

Ryan A Henry

Patrick Schreiner

Atsushi Matsuda

Alfonso G Fernandez

David Finkelstein

Margaret Campbell

Satish Kallappagoudar

Carolyn M Jablonowski

Andrew J Andrews

Yasushi Hiraoka

Janet F Partridge

Affiliations

Soon will be listed here.

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.

Citing Articles

Oncohistone H3 E97K mutation facilitates CENP-A mislocalization and chromosomal instability in budding yeast.

Ohkuni K, Au W, Kazi A, Balachandra V, Basrai M Nucleic Acids Res. 2025; 53(4).

PMID: 39945320 PMC: 11822376. DOI: 10.1093/nar/gkaf083.

Histone H3E50K remodels chromatin to confer oncogenic activity and support an EMT phenotype.

Sad K, Fawwal D, Jones C, Hill E, Skinner K, Adams M NAR Cancer. 2025; 7(1):zcaf002.

PMID: 39901931 PMC: 11788928. DOI: 10.1093/narcan/zcaf002.

Emerging roles of cancer-associated histone mutations in genomic instabilities.

Yadav P, Jain R, Yadav R Front Cell Dev Biol. 2024; 12:1455572.

PMID: 39439908 PMC: 11494296. DOI: 10.3389/fcell.2024.1455572.

Epigenetic reprogramming in pediatric gliomas: from molecular mechanisms to therapeutic implications.

Haase S, Carney S, Varela M, Mukherji D, Zhu Z, Li Y Trends Cancer. 2024; 10(12):1147-1160.

PMID: 39394009 PMC: 11631670. DOI: 10.1016/j.trecan.2024.09.007.

Histone H3 mutations and their impact on genome stability maintenance.

Caeiro L, Verdun R, Morey L Biochem Soc Trans. 2024; 52(5):2179-2191.

PMID: 39248209 PMC: 11580799. DOI: 10.1042/BST20240177.

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