ArticleThe Journal of biological chemistry2016
Structure/Function Analysis of Recurrent Mutations in SETD2 Protein Reveals a Critical and Conserved Role for a SET Domain Residue in Maintaining Protein Stability and Histone H3 Lys-36 Trimethylation.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 87 citations in OpenAlex.
- Cryptic transcription in aging.iScience · 2026Review
- SETD2 Deficiency Drives Mitochondrial DNA Leakage and Creates a Druggable Dependency on BCL-xL in Clear Cell Renal Cell Carcinoma.Cancer research · 2026Article
- Relationship between the distribution of LEDGF along genes and positions of HIV-1 DNA integration.mBio · 2026Article
- Essential genetic mutations impair DNA damage repair and modulate tumor immune microenvironment in ccRCC.MedScience · 2026Review
- Article
- The SETD2 L1609P mutation found in leukemia disrupts methyltransferase activity and reduces histone H3K36 trimethylation.The Journal of biological chemistry · 2026Article
- Loss of SETD2-mediated H3K36me3 Drives CD8Research (Washington, D.C.) · 2026Article
- The emerging paradigms of SETD family enzymes as epigenetic regulators of the immune response in inflammatory diseases.Frontiers in immunology · 2026Review
- Emerging role of SETD2 in the development and function of immune cells.Genes & diseases · 2025Review
- SETD2 suppresses tumorigenesis in a KRASeLife · 2025Article
- A SETD2-CDK1-lamin axis maintains nuclear morphology and genome stability.Nature cell biology · 2025Article
- Loss of SETD2 in wild-type VHL clear cell renal cell carcinoma sensitizes cells to STF-62247 and leads to DNA damage, cell cycle arrest, and cell death characteristic of pyroptosis.Molecular oncology · 2025Article
- Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications.Nature genetics · 2024Article
- Tumor cell-intrinsic SETD2 inactivation sensitizes cancer cells to immune checkpoint blockade through the NR2F1-STAT1 pathway.Journal for immunotherapy of cancer · 2023Article
- Tumor-suppressive functions of protein lysine methyltransferases.Experimental & molecular medicine · 2023Review
- The SETD2 Methyltransferase Supports Productive HPV31 Replication through the LEDGF/CtIP/Rad51 Pathway.Journal of virology · 2023Article
- A novelFrontiers in genetics · 2023Article
- Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma.Frontiers in oncology · 2023Review
- Clinical and genetic features of luscan-lumish syndrome associated with a novel de novo variant ofFrontiers in genetics · 2023Article
- Putative SET-domain methyltransferases inVirulence · 2022Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
The yeast Set2 histone methyltransferase is a critical enzyme that plays a number of key roles in gene transcription and DNA repair. Recently, the human homologue, SETD2, was found to be recurrently mutated in a significant percentage of renal cell carcinomas, raising the possibility that the activity of SETD2 is tumor-suppressive. Using budding yeast and human cell line model systems, we examined the functional significance of two evolutionarily conserved residues in SETD2 that are recurrently mutated in human cancers. Whereas one of these mutations (R2510H), located in the Set2 Rpb1 interaction domain, did not result in an observable defect in SETD2 enzymatic function, a second mutation in the catalytic domain of this enzyme (R1625C) resulted in a complete loss of histone H3 Lys-36 trimethylation (H3K36me3). This mutant showed unchanged thermal stability as compared with the wild type protein but diminished binding to the histone H3 tail. Surprisingly, mutation of the conserved residue in Set2 (R195C) similarly resulted in a complete loss of H3K36me3 but did not affect dimethylated histone H3 Lys-36 (H3K36me2) or functions associated with H3K36me2 in yeast. Collectively, these data imply a critical role for Arg-1625 in maintaining the protein interaction with H3 and specific H3K36me3 function of this enzyme, which is conserved from yeast to humans. They also may provide a refined biochemical explanation for how H3K36me3 loss leads to genomic instability and cancer.
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Registered trials
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.