SETD2

About SETD2

SETD2 on chromosome 3p21.31 encodes a histone methyltransferase that is the only enzyme known to produce trimethylation of histone H3 at lysine 36, the H3K36me3 mark. SETD2 travels with RNA polymerase II, and H3K36me3 accumulates over the bodies of actively transcribed genes, where it helps regulate transcription elongation, prevents spurious transcription from within genes, influences RNA splicing, and recruits DNA repair factors. Through these roles H3K36me3 links chromatin state to genome stability, for example by recruiting the mismatch repair protein MSH6 and supporting homologous recombination. SETD2 is a tumor suppressor that lies near VHL on the short arm of chromosome 3, a region commonly lost in clear cell renal cell carcinoma, and mutations inactivating the remaining copy occur in a notable minority of these tumors. SETD2 mutations are also found in some leukemias, particularly relapsed or high risk acute lymphoblastic leukemia, in gliomas of children and young adults, and in other cancers. Germline SETD2 variants cause Luscan Lumish syndrome, an overgrowth and intellectual disability disorder resembling Sotos syndrome, which itself is caused by the related H3K36 methyltransferase gene NSD1, and other germline variants cause distinct neurodevelopmental syndromes. Synthetic lethal strategies for SETD2 deficient tumors are under study.