SETD2 Gene

SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) is a protein coding gene located on chromosome 3p21.31. SETD2 is the only human gene responsible for the trimethylation of lysine 36 of histone H3 (H3K36). The effects of this histone modification are determined by H3K36me3 readers that recruit protein complexes to carry out specific processes, including transcription elongation, RNA processing, and DNA repair. SETD2 mediates the methylation of proteins, such as tubulins and STAT1, in addition to histone methylation.

Human SETD2 is a methyltransferase with 2 major isoforms: isoform 1 consists of 2,564 amino acids and has a molecular weight of 287.5 kDa. Isoform 2 is 44 residues shorter than isoform 1 at the N-terminus and consists of 2520 amino acids with a molecular weight of 282.6 kDa. SETD2 is a lysine methyltransferase and a transcriptional regulator involved in histone modification, DNA repair, mRNA regulation, genome stability, alternative splicing, and interferon-α signaling.

Methyltransferase acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required for recruitment of the MSH6 subunit of the MutS-alpha complex: early recruitment of the MutS-alpha complex to chromatin to be replicated allows rapid identification of mismatch DNA. This allows the "mismatch repair response" to be initiated.

SETD2- mutations are associated with clear cell renal cell cancer (Li J et al. 2016; Piva Fet al. 2015), hepatosplenic T-cell lymphoma, and peripheral T-cell lymphoma (NOS) (Ji MM et al. 2018; Yabe M et al. 2018).

Diseases associated with SETD2 include the tall stature syndromes Luscan-Lumish syndrome and Sotos syndrome 2 (Marzin Pet al. 2019).

1. Ji MM et al (2018) Histone modifier gene mutations in peripheral T-cell lymphoma not otherwise specified. Haematologica 103: 679-687.
2. Li J et al. (2016) SETD2: an epigenetic modifier with tumor suppressor functionality. Oncotarget 7(:50719-50734.
3. Marzin Pet al (2019) SETD2 related overgrowth syndrome: presentation of four new patients and review of the literature. Am J Med Genet C Semin Med Genet181:509-518.
4. Piva Fet al. (2015) BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies. Expert Rev Mol Diagn 15:1201-1210.
5. Sun J et al (2020) Recurrent SETD2 mutation in NPM1-mutated acute myeloid leukemia. Biomark Res 8: 62.
6. Yabe M et al (2018) Hepatosplenic T-cell lymphoma: a review of clinicopathologic features, pathogenesis, and prognostic factors. Hum Pathol. 74:5-16.