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SET domain-containing 2, histone lysine methyltransferase (SETD2)
- Target
- SETD2
- Molecular classification
- Enzyme, Protein lysine methyltransferase, Histone methyltransferase, Epigenetic regulator
01
Overview
SET domain-containing 2, histone lysine methyltransferase (SETD2), is an enzyme responsible for the trimethylation of lysine 36 in histone H3 (H3K36me3) in mammals[1][2][3][4][5][6][7]. SETD2 is the exclusive H3K36 trimethyltransferase in humans, acting as a critical epigenetic regulator that affects gene expression, alternative mRNA splicing, chromatin stability, DNA repair, genome maintenance, and development[1][2][4][5][7]. It also methylates certain non-histone proteins, impacting diverse cellular processes such as cell division and immune response[3][6]. Germline or somatic mutations in SETD2 are implicated in multiple human cancers and neurodevelopmental disorders. Loss of SETD2 function is associated with DNA repair defects, genomic instability, aberrant transcription, and altered cell fate decisions, making it an important tumor suppressor and a potential, though clinically unexplored, therapeutic target[1][4][5].
- Other names
- SETD2KIAA1732HYPBSET2 (in yeast)
02
Mechanism of action
Inhibition or modulation of methyltransferase activity; Modulation of epigenetic marks (altering H3K36me3 levels); Potential synthetic lethality in SETD2-deficient cancers (emerging research)
03
Biological functions
Histone methylation (notably H3K36 trimethylation, H3K36me3)Regulation of transcriptionAlternative splicingDNA double-strand break repairDNA methylationMaintenance of genomic stabilityCell cycle regulationRegulation of autophagyNon-histone protein methylation (e.g. α-tubulin, STAT1)Prevention of cryptic transcriptionCNS development
04
Disease associations
Cancer (including clear cell renal cell carcinoma, glioma, leukemia, lung, and other tumors)Neurodevelopmental disorders (e.g., Luscan–Lumish syndrome)Possibly involved in inflammation and immune response
05
Safety considerations
Loss of SETD2 function associated with genomic instability, impaired DNA repair, developmental defects, and increased cancer risk[1][5].Therapeutic inhibition could risk promoting tumorigenesis or impairing normal development; safety concerns not characterized due to lack of SETD2-selective therapeutics.
06
Interacting drugs
No FDA-approved drugs currently target SETD2 directly as a programmed mechanism[5].
1 more in the full profile.
07
Biomarkers
H3K36me3 (loss as biomarker of SETD2 dysfunction)Mutational status of SETD2 for cancer prognosis (especially in renal cell carcinoma and other tumors)SETD2 mutation or loss as biomarker for eligibility in clinical trials for agents targeting DNA repair deficiencies
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