OncoSignal
Live from Open Targets Platform, fetched 2026-11-11 22:40 UTC. Every row links to its source record.

SETD2 SET domain containing 2, histone lysine methyltransferase

ENSG00000181555 · protein coding · Open Targets profile

Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate (PubMed:16118227, PubMed:19141475, PubMed:21526191, PubMed:21792193, PubMed:23043551, PubMed:27474439). It is capable of trimethylating unmethylated H3K36 (H3K36me0) in vitro (PubMed:19332550). Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation (By similarity). Plays a role in chromatin structure modulation during elongation by coordinating recruitment of the FACT complex and by interacting with hyperphosphorylated POLR2A (PubMed:23325844). Acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required to recruit MSH6 subunit of the MutS alpha complex: early recruitment of the MutS alpha complex to chromatin to be replicated allows a quick identification of mismatch DNA to initiate the mismatch repair reaction (PubMed:23622243). Required for DNA double-strand break repair in response to DNA damage: acts by mediating formation of H3K36me3, promoting recruitment of RAD51 and DNA repair via homologous recombination (HR) (PubMed:24843002). Acts as a tumor suppressor (PubMed:24509477). H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A (PubMed:27317772). H3K36me3 is also enhanced in intron-containing genes, suggesting that SETD2 recruitment is enhanced by splicing and that splicing is coupled to recruitment of elongating RNA polymerase (PubMed:21792193). Required during angiogenesis (By similarity). Required for endoderm development by promoting embryonic stem cell differentiation toward endoderm: acts by mediating formation of H3K36me3 in distal promoter regions of FGFR3, leading to regulate transcription initiation of FGFR3 (By similarity). In addition to histones, also mediates methylation of other proteins, such as tubulins and STAT1 (PubMed:27518565, PubMed:28753426). Trimethylates 'Lys-40' of alpha-tubulins such as TUBA1B (alpha- TubK40me3); alpha-TubK40me3 is required for normal mitosis and cytokinesis and may be a specific tag in cytoskeletal remodeling (PubMed:27518565). Involved in interferon-alpha-induced antiviral defense by mediating both monomethylation of STAT1 at 'Lys-525' and catalyzing H3K36me3 on promoters of some interferon-stimulated genes (ISGs) to activate gene transcription (PubMed:28753426). {ECO:0000250|UniProtKB:E9Q5F9, ECO:0000269|PubMed:16118227, ECO:0000269|PubMed:19141475, ECO:0000269|PubMed:21526191, ECO:0000269|PubMed:21792193, ECO:0000269|PubMed:23043551, ECO:0000269|PubMed:23325844, ECO:0000269|PubMed:23622243, ECO:0000269|PubMed:24509477, ECO:0000269|PubMed:24843002, ECO:0000269|PubMed:27317772, ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:27518565, ECO:0000269|PubMed:28753426}.

In 15 of 15 cancers, the evidence for SETD2 comes mainly from mutations found in tumours

Each row is a cancer, strongest overall evidence first. The two dots show how strong the inherited (germline) and tumour-mutation (somatic) evidence is; the line between them is the gap.

Inherited (germline) variantsMutations in tumours (somatic)
00.250.50.751clear cell renal carcinomaclear cell renal carcinomaclear cell renal carcinoma: somatic 0.78pleural mesotheliomapleural mesotheliomapleural mesothelioma: somatic 0.74lung adenocarcinomalung adenocarcinomalung adenocarcinoma: somatic 0.64B-cell chronic lymphocytic leukemiaB-cell chronic lymphocytic leukemiaB-cell chronic lymphocytic leukemia: somatic 0.64acute lymphoblastic leukemiaacute lymphoblastic leukemiaacute lymphoblastic leukemia: somatic 0.58acute lymphoblastic leukemia: germline 0.48renal cell carcinomarenal cell carcinomarenal cell carcinoma: somatic 0.58renal cell carcinoma: germline 0.38melanomamelanomamelanoma: somatic 0.58pancreatic neuroendocrine tumorpancreatic neuroendocrine tumorpancreatic neuroendocrine tumor: somatic 0.58non-small cell lung carcinomanon-small cell lung carcinomanon-small cell lung carcinoma: somatic 0.57cutaneous melanomacutaneous melanomacutaneous melanoma: somatic 0.55kidney neoplasmkidney neoplasmkidney neoplasm: somatic 0.61acute myeloid leukemiaacute myeloid leukemiaacute myeloid leukemia: somatic 0.46acute myeloid leukemia: germline 0.36FibroadenomaFibroadenomaFibroadenoma: somatic 0.61hemangioblastomahemangioblastomahemangioblastoma: somatic 0.61breast phyllodes tumorbreast phyllodes tumorbreast phyllodes tumor: somatic 0.61

Scores run from 0 (no evidence) to 1 (strongest). A missing dot at 0 means Open Targets holds no evidence of that kind. Source: Open Targets Platform, fetched live.

Tractability

Small molecule
Structure with Ligand, High-Quality Ligand
PROTAC
UniProt Ubiquitination, Database Ubiquitination, Half-life Data, Small Molecule Binder

gnomAD loss of function constraint: o/e 0.12806999683380127 (upper bound 0.17284999787807465). Low values mean loss of function is poorly tolerated, a safety flag for inhibition.

Who runs trials of these drugs

No named investigators on registry trials of SETD2's approved or late-stage drugs in the last three years.

No terminated, withdrawn or suspended trials of SETD2's drugs are registered

All 0 drugs and clinical candidates as a table

Each drug, stage and indication links to its Open Targets record, where the trials and approvals behind it are listed. Salt forms (for example a mesylate) are listed as Open Targets records them, as separate entries.

DrugTypeHighest stageIndicationsSource records
No drugs or clinical candidates recorded.