Histone-lysine N-methyltransferase SETD2 (SETD2) (SETD2)

Histone-lysine N-methyltransferase SETD2 (SETD2) is the primary enzyme responsible for the trimethylation of histone H3 at lysine 36 (H3K36me3) in mammals. This epigenetic modification is essential for coordinating transcription elongation, DNA mismatch repair, and alternative splicing, thereby maintaining genomic integrity. Beyond its role in chromatin, SETD2 also methylates non-histone proteins like alpha-tubulin and STAT1, influencing microtubule stability and immune signaling. SETD2 is frequently mutated or lost in various malignancies, particularly clear cell renal cell carcinoma (ccRCC) and certain leukemias, where it functions as a tumor suppressor. Loss of SETD2 activity leads to H3K36me3 depletion, genomic instability, and resistance to conventional chemotherapies. While direct inhibitors of SETD2 are under investigation, current therapeutic strategies primarily focus on synthetic lethality, using agents like WEE1 or PARP inhibitors to selectively target SETD2-deficient cancer cells.

Other names

SET domain containing 2HIF-1 alpha-binding proteinHuntington-interacting protein 1HIP-1KMT3AHYPBKIAA1732Protein-lysine N-methyltransferase SETD2Huntingtin-interacting protein BLysine N-methyltransferase 3AHuntingtin yeast partner BFLJ23184P231HBPSET2

Synthetic lethality in SETD2-deficient cells (e.g., via WEE1 or PARP inhibition); Inhibition of histone H3 lysine 36 trimethylation activity.