SET7/9 mediated methylation of non-histone proteins in mammalian cells

New England Biolabs Inc, Ipswich, MA, USA.
Epigenetics: official journal of the DNA Methylation Society (Impact Factor: 4.78). 09/2009; 4(6):383-7. DOI: 10.4161/epi.4.6.9450
Source: PubMed


Lysine methylation has emerged as a major posttranslational modification for histones in eukaryotes. Crosstalk between lysine methylation and other posttranslational modifications is crucial for transcriptional gene regulation and epigenetic inheritance. In addition to histones, several other cellular proteins including transcription factors, tumor suppressor and membrane-associated receptors are subject to lysine methylation. SET7/9 plays a prominent role in lysine methylation of histone and non-histone proteins. Recent reports have suggested a new mechanism of epigenetic gene regulation via SET7/9 modulated DNMT1 methylation. In this mechanism, SET7/9 may methylate DNMT1 leading to proteasome mediated protein degradation, and antagonist lysine specific demethylase (LSD), may prevent this degradation by removing the methyl mark. Thus a fine-tuning and balance between cellular SET7/9 and LSD interaction with DNMT1 may be means for epigenetic gene regulation.

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    • "Set7 is a KMT that was initially identified as a monomethylase of histone H3 lysine 4 (H3K4) in vitro (Wang et al., 2001). However , because Set7 is unable to methylate nucleosomes at H3K4 (Chuikov et al., 2004) and Setd7 À/À mouse embryonic fibroblasts (MEFs) have normal levels of H3K4 methylation (Lehnertz et al., 2011), it is more likely that the primary role for Set7 is methylation of nonhistone substrates (Pradhan et al., 2009). Indeed, Set7 has been shown to methylate and alter function of a wide variety of proteins including Dnmt1, Taf10, p53, Stat3, and NF-kB in vitro (Chuikov et al., 2004; Ea and Baltimore, 2009; Estè ve et al., 2009; Kouskouti et al., 2004; Kurash et al., 2008; Yang et al., 2009, 2010a, 2010b). "
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    ABSTRACT: Methylation of nonhistone proteins is emerging as a regulatory mechanism to control protein function. Set7 (Setd7) is a SET-domain-containing lysine methyltransferase that methylates and alters function of a variety of proteins in vitro, but the in vivo relevance has not been established. We found that Set7 is a modifier of the Hippo pathway. Mice that lack Set7 have a larger progenitor compartment in the intestine, coinciding with increased expression of Yes-associated protein (Yap) target genes. Mechanistically, monomethylation of lysine 494 of Yap is critical for cytoplasmic retention. These results identify a methylation-dependent checkpoint in the Hippo pathway.
    Developmental Cell 07/2013; 26(2). DOI:10.1016/j.devcel.2013.05.025 · 9.71 Impact Factor
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    • "HKMT7 contains only one protein, Set7/9, which monomethylates histone at H3-K4 [68]. Set7/9 methylates also non-histone proteins, including p53, DNA methyltransferase 1 (DNMT1), nuclear factor kappa B (NFkB) and nuclear hormone estrogen receptor alpha (ER) [59]. HKMT8 includes only one member, RIZ1. "
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    ABSTRACT: Epigenetics is defined as heritable changes in gene activity and expression that occur without alteration in DNA sequence. The gene transcription is strictly correlated to chromatin structure, which could undergo to covalent modifications of histones involving acetylation, methylation, phosphorylation and ubiquitination. Alterations in histones are implicated in many diseases, included cancer, by leading to tumor suppressor silencing or pro-apoptotic proteins downregulation. Although post-translational addition of methyl groups to the histone lysine has been discovered three decades ago, the importance of this epigenetic modification is emerging only in the last few years. Thenceforward histone methyltransferase inhibitors have been developed as potential therapeutic cancer agents. It should not be long before some selective inhibitors make their way into clinical trials. This review is mainly focused on the evolution in the development of new epigenetic modifier molecules modulating histone marks.
    Current Medicinal Chemistry 11/2012; 20(2). DOI:10.2174/0929867311320020002 · 3.85 Impact Factor
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    • "Because the mono-methyltransferase SETD7 has been reported to methylate numerous substrates [11,12], we first sought to examine the feasibility of the protein array system by testing the activity of SETD7. To this end, arrays were incubated overnight with recombinant SETD7 or with GST as a negative control, probed with the pan-methyl antibody, and scanned for analysis. "
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    ABSTRACT: ABSTRACT: Signaling via protein lysine methylation has been proposed to play a central role in the regulation of many physiologic and pathologic programs. In contrast to other post-translational modifications such as phosphorylation, proteome-wide approaches to investigate lysine methylation networks do not exist. In the current study, we used the ProtoArray® platform, containing over 9,500 human proteins, and developed and optimized a system for proteome-wide identification of novel methylation events catalyzed by the protein lysine methyltransferase (PKMT) SETD6. This enzyme had previously been shown to methylate the transcription factor RelA, but it was not known whether SETD6 had other substrates. By using two independent detection approaches, we identified novel candidate substrates for SETD6, and verified that all targets tested in vitro and in cells were genuine substrates. We describe a novel proteome-wide methodology for the identification of new PKMT substrates. This technological advance may lead to a better understanding of the enzymatic activity and substrate specificity of the large number (more than 50) PKMTs present in the human proteome, most of which are uncharacterized.
    Epigenetics & Chromatin 10/2011; 4(1):19. DOI:10.1186/1756-8935-4-19 · 5.33 Impact Factor
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