Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
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.
Article activity feed
-
-
This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on January 18 2021, follows.
Summary
This is an exhaustive study of different phenotypes associated with Histone H3-G34 mutations in a fission yeast model. Because mutations at this site occur in certain human cancers, teasing apart their different phenotypes in a model system helps to understand their potential effects in pathology. The phenotypes vary widely, suggesting a key role for this residue in a variety of genome maintenance functions.
The authors systematically examine histone modifications, transcription, and use genetic and cytological assays to measure genome stability. The phenotypes vary widely, suggesting a key role for this residue in a variety of genome maintenance functions. Direct extrapolation to human cells is limited …
This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on January 18 2021, follows.
Summary
This is an exhaustive study of different phenotypes associated with Histone H3-G34 mutations in a fission yeast model. Because mutations at this site occur in certain human cancers, teasing apart their different phenotypes in a model system helps to understand their potential effects in pathology. The phenotypes vary widely, suggesting a key role for this residue in a variety of genome maintenance functions.
The authors systematically examine histone modifications, transcription, and use genetic and cytological assays to measure genome stability. The phenotypes vary widely, suggesting a key role for this residue in a variety of genome maintenance functions. Direct extrapolation to human cells is limited due to the absence of multiple H3 variants in fission yeast, and the absence of the PRC1/2 pathway. However, this is balanced by the rapid and thorough analysis of numerous variants that is enabled in this model system.
It is not possible to draw a simple model as there is little consistency in the phenotypes. This suggests that the G34 residue independently affects multiple activities. These will require laborious efforts to tease out.
Essential Revisions
This is overall a technically very well done paper with a variety of methods to examine different mutations in H3-G34. The strength is the consistent approach applied to numerous mutations. However, as there is no single response, it's rather descriptive overall. We have no major concerns about the data, but feel that the conclusions need to be tempered in two areas where the assays were not direct.
In the absence of NHEJ repair assays it needs to be noted that conclusions about NHEJ proficiency based on drug sensiutivty are indirect.2)
The authors imply that the H3G34 mutants affect the activity of the Set2 H3K36 methyltransferase. In the absence of an in vitro H3K36 methylation assay on the mutant histones with recombinant or affinity purified Set2 the authors need to note that this conclusion is speculative as they have not measured it directly.
-
