Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail
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.
-
Surprising Phenotypic Diversity of Cancer-associated mutations at Gly 34 in the Histone H3 tailNCBI Gene Expression Omnibus, GSE162572.
-
S. pombe acetyltransferase mutants identifies redundant pathways of gene regulation, dual-channel datasetNCBI Gene Expression Omnibus, GSE17259.
-
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.
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.
Metrics
-
- 1,765
- views
-
- 308
- downloads
-
- 24
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cancer Biology
- Chromosomes and Gene Expression
MYC family oncoproteins regulate the expression of a large number of genes and broadly stimulate elongation by RNA polymerase II (RNAPII). While the factors that control the chromatin association of MYC proteins are well understood, much less is known about how interacting proteins mediate MYC’s effects on transcription. Here, we show that TFIIIC, an architectural protein complex that controls the three-dimensional chromatin organisation at its target sites, binds directly to the amino-terminal transcriptional regulatory domain of MYCN. Surprisingly, TFIIIC has no discernible role in MYCN-dependent gene expression and transcription elongation. Instead, MYCN and TFIIIC preferentially bind to promoters with paused RNAPII and globally limit the accumulation of non-phosphorylated RNAPII at promoters. Consistent with its ubiquitous role in transcription, MYCN broadly participates in hubs of active promoters. Depletion of TFIIIC further increases MYCN localisation to these hubs. This increase correlates with a failure of the nuclear exosome and BRCA1, both of which are involved in nascent RNA degradation, to localise to active promoters. Our data suggest that MYCN and TFIIIC exert an censoring function in early transcription that limits promoter accumulation of inactive RNAPII and facilitates promoter-proximal degradation of nascent RNA.
-
- Chromosomes and Gene Expression
Since double-stranded RNA (dsRNA) is effective for silencing a wide variety of genes, all genes are typically considered equivalent targets for such RNA interference (RNAi). Yet, loss of some regulators of RNAi in the nematode Caenorhabditis elegans can selectively impair the silencing of some genes. Here, we show that such selective requirements can be explained by an intersecting network of regulators acting on genes with differences in their RNA metabolism. In this network, the Maelstrom domain-containing protein RDE-10, the intrinsically disordered protein MUT-16, and the Argonaute protein NRDE-3 work together so that any two are required for silencing one somatic gene, but each is singly required for silencing another somatic gene, where only the requirement for NRDE-3 can be overcome by enhanced dsRNA processing. Quantitative models and their exploratory simulations led us to find that (1) changing cis-regulatory elements of the target gene can reduce the dependence on NRDE-3, (2) animals can recover from silencing in non-dividing cells, and (3) cleavage and tailing of mRNAs with UG dinucleotides, which makes them templates for amplifying small RNAs, are enriched within ‘pUG zones’ matching the dsRNA. Similar crosstalk between pathways and restricted amplification could result in apparently selective silencing by endogenous RNAs.