SETD2

SETD2 is a human gene that encodes the histone-lysine N-methyltransferase SET domain-containing 2. It catalyzes the trimethylation of histone H3 on lysine 36 (H3K36me3), a chromatin mark enriched in the bodies of actively transcribed genes and associated with transcription elongation, RNA processing, and the DNA damage response. The SETD2 protein is a large nuclear enzyme, approximately 2,500 amino acids in length, with a C-terminal SET domain responsible for catalytic activity and a Set2-Rpb1 interacting (SRI) domain that binds RNA polymerase II to coordinate methylation with transcription.

In humans, SETD2 is located on chromosome 3p21.31 and is broadly expressed. It is the primary enzyme responsible for generating H3K36me3 in most genomic contexts; other methylation states of H3K36 (such as me1/me2) can be deposited by other methyltransferases, including members of the NSD family.

Biological roles of SETD2 include supporting transcriptional elongation, co-transcriptional RNA processing, and the DNA damage response. H3K36me3 helps recruit factors involved in mismatch repair and homologous recombination, contributing to genome stability. SETD2 can interact with MSH6 and other DNA repair proteins, linking chromatin modification to DNA repair pathways.

Clinical significance of SETD2 centers on its frequent inactivation in cancer. Mutations or deletions of SETD2 are observed in cancers such as clear cell renal cell carcinoma, gliomas, and certain leukemias. Loss of SETD2 function reduces H3K36me3, impairs DNA repair, and promotes genomic instability, with potential implications for prognosis and response to DNA-damaging therapies. Ongoing research continues to clarify its roles in cancer biology and development.