Characterization of a novel WHSC1-associated SET domain protein with H3K4 and H3K27 methyltransferase activity

Kim, Sung Mi; Kee, Hae Jin; Eom, Gwang Hyeon; Choe, Nak Won; Kim, Ji Young; Kim, Young Soo; Kim, Seong Ki; Kook, Hoon; Kook, Hyun; Seo, Sang-Beom

doi:10.1016/j.bbrc.2006.04.095

Cited by 65 publications

(53 citation statements)

References 14 publications

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“…A significant increase in H3K36me3 by NSD2 at promoter regions has also recently been demonstrated [4], but potentially ruled-out in another study [20]. In addition, NSD2 has been shown to methylate H3K4, H3K27, and H4K44 [5,6,[36][37][38]. Discrepancies regarding NSD3 methylation activities on H3K4, H3K27, and H3K36 have also been reported [6,24,[39][40][41].…”

Section: Introductionmentioning

confidence: 85%

“…In addition, NSD2 has been shown to methylate H3K4, H3K27, and H4K44 [5,6,[36][37][38]. Discrepancies regarding NSD3 methylation activities on H3K4, H3K27, and H3K36 have also been reported [6,24,[39][40][41]. Complicating the mechanisms further, both NSD1 and NSD2 have been shown to methylate NF-κB [8,42].…”

Section: Introductionmentioning

confidence: 95%

“…Histone lysine methyltransferases (HMTases) are transcriptional coregulators that target specific lysines on histones H3 and H4, and can transfer up to three methyl groups (Kme1, Kme2, and Kme3) [1]. However, the molecular mechanisms of histone mark recognition remain unclear [2][3][4][5][6]. Epigenetic marks on H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20 have been reported to play primary roles in regulating the chromatin and contribute to the histone code that is still obscure [7].…”

Section: Introductionmentioning

confidence: 99%

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In vitro histone lysine methylation by NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L

Morishita

Mevius

Luccio

2014

BMC Structural Biology

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Background: Histone lysine methylation has a pivotal role in regulating the chromatin. Histone modifiers, including histone methyl transferases (HMTases), have clear roles in human carcinogenesis but the extent of their functions and regulation are not well understood. The NSD family of HMTases comprised of three members (NSD1, NSD2/ MMSET/WHSC1, and NSD3/WHSC1L) are oncogenes aberrantly expressed in several cancers, suggesting their potential to serve as novel therapeutic targets. However, the substrate specificity of the NSDs and the molecular mechanism of histones H3 and H4 recognition and methylation have not yet been established.

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Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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In vitro histone lysine methylation by NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L

Morishita

Mevius

Luccio

2014

BMC Structural Biology

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“…(57). ** Although UniProt also describes this as SET2, the function of this protein does not match its subfamily description; it has H3K4 and H3K27 activity (58). *** This protein has also been shown to have H3K27 activity (59).…”

Section: Analysis Of Potential Substrates For Human Seven-␤-strandmentioning

confidence: 99%

“…Class II proteins NSD1 and WHSC1 have also been shown to methylate H4K20. The WHSC1L1 protein, a homolog of WHSC1, is exceptional because it displays both H3K4 and H3K27 activity (58). Proteins in the UniProt TRX/MLL subfamily, which methylate H3K4, fall into Classes III and IV.…”

Section: Analysis Of Potential Substrates For Human Seven-␤-strandmentioning

confidence: 99%

Uncovering the Human Methyltransferasome

Petrossian¹,

Clarke²

2011

Molecular & Cellular Proteomics

247

268

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We present a comprehensive analysis of the human methyltransferasome. Primary sequences, predicted secondary structures, and solved crystal structures of known methyltransferases were analyzed by hidden Markov models, Fisher-based statistical matrices, and fold recognition prediction-based threading algorithms to create a model, or profile, of each methyltransferase superfamily. These profiles were used to scan the human proteome database and detect novel methyltransferases. 208 proteins in the human genome are now identified as known or putative methyltransferases, including 38 proteins that were not annotated previously. To date, 30% of these proteins have been linked to disease states. Possible substrates of methylation for all of the SET domain and SPOUT methyltransferases as well as 100 of the 131 seven-␤-strand methyltransferases were surmised from sequence similarity clusters based on alignments of the substrate-specific domains. Molecular & Cellular Proteomics 10: 10.1074/mcp.M110.000976, 1-12, 2011.A significant percentage of proteins across all organisms are enzymes that catalyze the transfer of a methyl group from the cofactor S-adenosylmethionine to a substrate (1-5). In yeast, these proteins make up about 1.2% of all gene products (6, 7). The ability of methyltransferases to use a variety of different substrates, including RNA, DNA, lipids, small molecules, and proteins, is responsible for their diverse roles in different biological pathways (1-3). Methyltransferases have been shown to be essential in epigenetic control, lipid biosynthesis, protein repair, hormone inactivation, and tissue differentiation (8 -14). The identification of new enzymes may allow the delineation of additional pathways and modes of regulation as well as increase our understanding of S-adenosylmethionine metabolism.Although there are hundreds of known substrates for these reactions, methyltransferases are found in a small number of distinct structural arrangements that are used to classify them into superfamilies (2,3,5,6,15). Proteins in each superfamily also share conserved amino acid sequences. The seven-␤-strand superfamily (also referred to as "Class I" methyltransferases) is the most abundant. These proteins catalyze a wide array of substrates and feature a Rossmann-like structural core (2,3,5,6,15). The SPOUT methyltransferase superfamily contains a distinctive knot structure and methylates RNA substrates (16). SET domain methyltransferases catalyze the methylation of protein lysine residues with histones and ribosomal proteins as major targets (17)(18)(19). Smaller superfamilies with at least one three-dimensional structure available include the precorrin-like methyltransferases (20), the radical SAM 1 methyltransferases (21, 22), the MetH activation domain (23), the Tyw3 protein involved in wybutosine synthesis (24), and the homocysteine methyltransferases (25-27). Lastly, an integral membrane methyltransferase family has been defined by sequence alone where no three-dimensional structure is yet available (28,29).Ad...

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