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Histone-lysine N-methyltransferase SETD2

Definition:

Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate. It is capable of trimethylating unmethylated H3K36 (H3K36me0) in vitro. 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. 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. 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). Acts as a tumor suppressor. H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A. 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. 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. 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. 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.; (Microbial infection) Recruited to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression.

References:

[1]. In Young Park, et al. Dual Chromatin and Cytoskeletal Remodeling by SETD2. Cell. 2016 Aug 11;166(4):950-962. [Content Brief]

[2]. Camille Tlemsani, et al. SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. J Med Genet. 2016 Nov;53(11):743-751. [Content Brief]

[3]. Shuang Yang, et al. Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase. Genes Dev. 2016 Jul 15;30(14):1611-6. [Content Brief]

[4]. Xiaofan Zhu, et al. Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat Genet. 2014 Mar;46(3):287-93. [Content Brief]

[5]. Feng Li, et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell. 2013 Apr 25;153(3):590-600. [Content Brief]

[6]. Sílvia Carvalho, et al. SETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint. Elife. 2014 May 6;3:e02482. [Content Brief]

[7]. Kun Chen, et al. Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity. Cell. 2017 Jul 27;170(3):492-506.e14. [Content Brief]

[8]. Maria A Hahn, et al. Relationship between gene body DNA methylation and intragenic H3K9me3 and H3K36me3 chromatin marks. PLoS One. 2011 Apr 19;6(4):e18844. [Content Brief]

[9]. S Rega, et al. Identification of the full-length huntingtin- interacting protein p231HBP/HYPB as a DNA-binding factor. Mol Cell Neurosci. 2001 Jul;18(1):68-79. [Content Brief]

[10]. Xiao-Jian Sun, et al. Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase. J Biol Chem. 2005 Oct 21;280(42):35261-71. [Content Brief]

[11]. Weihong Zheng, et al. Sinefungin derivatives as inhibitors and structure probes of protein lysine methyltransferase SETD2. J Am Chem Soc. 2012 Oct 31;134(43):18004-14. [Content Brief]

[12]. Sílvia Carvalho, et al. Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics during transcription. Nucleic Acids Res. 2013 Mar 1;41(5):2881-93. [Content Brief]

[13]. Sunnie M Yoh, et al. The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation. Genes Dev. 2008 Dec 15;22(24):3422-34. [Content Brief]

[14]. Sérgio Fernandes de Almeida, et al. Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Lys36. Nat Struct Mol Biol. 2011 Jul 26;18(9):977-83. [Content Brief]

[15]. Wen Yuan, et al. Heterogeneous nuclear ribonucleoprotein L Is a subunit of human KMT3a/Set2 complex required for H3 Lys-36 trimethylation activity in vivo. J Biol Chem. 2009 Jun 5;284(23):15701-7. [Content Brief]

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