ArticleProceedings of the National Academy of Sciences of the United States of America2018
Cancer-driving H3G34V/R/D mutations block H3K36 methylation and H3K36me3-MutSα interaction.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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Who cites it
73 citing papers in PubMed, 127 citations in OpenAlex.
- Epigenetic mechanisms and therapeutic advances in diffuse midline glioma (Review).Oncology reports · 2026Review
- G34R cancer mutation alters the conformational ensemble and dynamics of the histone H3.3 tails.Nucleic acids research · 2026Article
- Cancer histone H2A.Z missense mutations disrupt function through distinct local and allosteric effects.Research square · 2026Article
- Case Report: Identification of rareFrontiers in oncology · 2026Article
- The Bermuda Triangle of paediatric brain cancers: epigenetics, developmental timing window and cell of origin.Cancer metastasis reviews · 2025Review
- Cancer histone mutations impact protein binding and DNA repair with possible links to genomic instability.Nucleic acids research · 2025Article
- Outcomes From a Contemporary Mono-Institutional Cohort of Histone-Mutant Diffuse Hemispheric Glioma: A Rare and Aggressive Pediatric-Type High-Grade Primary Brain Tumor.Brain tumor research and treatment · 2025Article
- Characterization of oncohistone H2B variants in Schizosaccharomyces pombe reveals a key role of H2B monoubiquitination deficiency in genomic instability by altering gene expression.FEMS yeast research · 2025Article
- PALB2 deficiency may sensitize H3K27M-mutant pediatric HGG cells to BMN673/talazoparib.Frontiers in oncology · 2025Article
- (B)On(e)-cohistones and the epigenetic alterations at the root of bone cancer.Cell death and differentiation · 2025Review
- Aberrant histone modifications in pediatric brain tumors.Frontiers in oncology · 2025Review
- Histone H3 mutations and their impact on genome stability maintenance.Biochemical Society transactions · 2024Review
- Molecular and Pathological Features of Paediatric High-Grade Gliomas.International journal of molecular sciences · 2024Review
- Epigenetics to clinicopathological features: a bibliometric analysis of H3 G34-mutant diffuse hemispheric glioma literature.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2024Review
- Beyond the Usual Suspects: Examining the Role of Understudied Histone Variants in Breast Cancer.International journal of molecular sciences · 2024Review
- Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation.Nature communications · 2024Article
- DNA Repair in Nucleosomes: Insights from Histone Modifications and Mutants.International journal of molecular sciences · 2024Review
- Aberrant DNA repair reveals a vulnerability in histone H3.3-mutant brain tumors.Nucleic acids research · 2024Article
- Emerging roles of cancer-associated histone mutations in genomic instabilities.Frontiers in cell and developmental biology · 2024Review
- Therapeutically targeting the unique disease landscape of pediatric high-grade gliomas.Frontiers in oncology · 2024Review
13 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
Abstract
Somatic mutations on glycine 34 of histone H3 (H3G34) cause pediatric cancers, but the underlying oncogenic mechanism remains unknown. We demonstrate that substituting H3G34 with arginine, valine, or aspartate (H3G34R/V/D), which converts the non-side chain glycine to a large side chain-containing residue, blocks H3 lysine 36 (H3K36) dimethylation and trimethylation by histone methyltransferases, including SETD2, an H3K36-specific trimethyltransferase. Our structural analysis reveals that the H3 "G33-G34" motif is recognized by a narrow substrate channel, and that H3G34/R/V/D mutations impair the catalytic activity of SETD2 due to steric clashes that impede optimal SETD2-H3K36 interaction. H3G34R/V/D mutations also block H3K36me3 from interacting with mismatch repair (MMR) protein MutSα, preventing the recruitment of the MMR machinery to chromatin. Cells harboring H3G34R/V/D mutations display a mutator phenotype similar to that observed in MMR-defective cells. Therefore, H3G34R/V/D mutations promote genome instability and tumorigenesis by inhibiting MMR activity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.