Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail
Year: 2021
Type: article
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.
Source: eLife
DOI: 10.7554/elife.65369
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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: G1281772883, G216989177, G2484214792, G2541105955, Super-resolution imaging with distance measurement at 1 nm accuracy in live cells, G3083263895, G4050733389, G5415096612, G609259107, G621298182, G6928536118, G7000787819, G751896108, Molecular mechanisms for recognition and pairing of homologous chromosomes, The Role of Histone Chaperones in Histone Acetylation and Nucleosome Dynamics, G865138149, G9000013868, G9000015149, G9000086855, Cancer Center Support Grant (CCSG)
OpenAlex ID: W3126414462