InterPro domain: IPR044437

This entry represents the SET domain found in SETD2 from animals, ASHH2 from plants and Set2 from fungi. Proteins containing this domain are a group of histone methyltransferases that methylates histone H3 to form H3K36me [ 1 , 2 ].

Yeast Set2 is involved in transcription elongation as well as in transcription repression [ 3 ]. The methyltransferase activity of budding yeast Set2 requires the recruitment to the RNA polymerase II, which is CTK1 dependent [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. Plant ASHH2 is required for the correct expression of genes essential to reproductive development [ 11 ].

SETD2 acts as histone-lysine N-methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using demethylated 'Lys-36' (H3K36me2) as substrate [ 12 , 12 ]. SETD2 is also required for DNA double-strand break repair and activation of the p53-mediated checkpoint [ 13 ]. SETD2-inactivation has been linked to tumour development [ 14 ]. SETD2 also methylates alpha-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules. Methylation of microtubules occurs during mitosis and cytokinesis and can be ablated by SETD2 deletion, which causes mitotic spindle and cytokinesis defects, micronuclei, and polyploidy [ 15 ]. Moreover, SETD2 is also 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 [ 16 ].

SETD2 has been linked to several human diseases, including Renal cell carcinoma (RCC) [ 17 ], Luscan-Lumish syndrome (LLS) [ 18 ], Leukemia, acute lymphoblastic (ALL) [ 19 ] and Leukemia, acute myelogenous (AML) [ 20 , 21 ].

1. Set2 methylation of histone H3 lysine 36 suppresses histone exchange on transcribed genes. Nature 489, 452-5
2. The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation. Genes Dev. 22, 3422-34
3. Histone H3 K36 methylation is associated with transcription elongation in Schizosaccharomyces pombe. Eukaryotic Cell 4, 1446-54
4. The histone 3 lysine 36 methyltransferase, SET2, is involved in transcriptional elongation. Nucleic Acids Res. 31, 2475-82
5. Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. Mol. Cell. Biol. 22, 1298-306
6. Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast. Genes Dev. 17, 654-63
7. Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II. Mol. Cell. Biol. 23, 4207-18
8. Set2-catalyzed methylation of histone H3 represses basal expression of GAL4 in Saccharomyces cerevisiae. Mol. Cell. Biol. 23, 5972-8
9. A novel domain in Set2 mediates RNA polymerase II interaction and couples histone H3 K36 methylation with transcript elongation. Mol. Cell. Biol. 25, 3305-16
10. Dimethylation of histone H3 at lysine 36 demarcates regulatory and nonregulatory chromatin genome-wide. Mol. Cell. Biol. 25, 9447-59
11. The ASH1 HOMOLOG 2 (ASHH2) histone H3 methyltransferase is required for ovule and anther development in Arabidopsis. PLoS One 4, e7817
12. Molecular basis for the role of oncogenic histone mutations in modulating H3K36 methylation. Sci Rep 7, 43906
13. SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint. Elife 3, e02482
14. SETD2: an epigenetic modifier with tumor suppressor functionality. Oncotarget 7, 50719-50734
15. Dual Chromatin and Cytoskeletal Remodeling by SETD2. Cell 166, 950-962
16. Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity. Cell 170, 492-506.e14
17. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360-3
18. SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. J Med Genet 53, 743-751
19. Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia. Nat Commun 5, 3469
20. Solution structure of the Set2-Rpb1 interacting domain of human Set2 and its interaction with the hyperphosphorylated C-terminal domain of Rpb1. Proc. Natl. Acad. Sci. U.S.A. 102, 17636-41
21. Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat Genet 46, 287-93