Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail
- St Jude Children's Research Hospital, United States
- Fox Chase Cancer Center, United States
- National Institute of Information and Communications Technology, Japan
- Osaka University, Japan
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
-
- 1,871
- views
-
- 321
- downloads
-
- 31
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
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)
Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail
eLife 10:e65369.
https://doi.org/10.7554/eLife.65369
Further reading
-
- Chromosomes and Gene Expression
- Evolutionary Biology
Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.
-
- Chromosomes and Gene Expression
RNA interference (RNAi) is a conserved pathway that utilizes Argonaute proteins and their associated small RNAs to exert gene regulatory function on complementary transcripts. While the majority of germline-expressed RNAi proteins reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here, we find that the small RNA biogenesis machinery is spatially and temporally organized during Caenorhabditis elegans embryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we further demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.
