Structure of the Catalytic Domain of Human DOT1L, a Non-SET Domain Nucleosomal Histone Methyltransferase

Min, Jinrong; Feng, Qin; Li, Zhizhong; Zhang, Yi; Xu, Rui-Ming

doi:10.1016/s0092-8674(03)00114-4

Cited by 368 publications

(442 citation statements)

References 42 publications

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“…Structural and biochemical studies by Rui-Ming Xu and colleagues characterize a 4-Å methyl transfer channel partitioning the SAM-binding cavity from the putative substrate-binding site, which is formed by a substrate-binding loop (residues 301-311). This spatial organization is consistent with an in-line methyl transfer reaction, whereby a likely deprotonated acceptor lysine executes nucleophilic attack on the SAM methyl group 6 . EPZ004777 (Fig.…”

Section: Resultssupporting

confidence: 74%

“…The catalytic subunit of DOT1L comprises its first 416 residues 6 . Mono-and dimethylation of H3K79 is dependent on SAM (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1f-g). Importantly, Tyr312 and Thr139 are considered key partners in forming the methyl transfer channel, and mutation of Tyr312 to Ala abrogates methyltransferase activity 6 . In the presence of EPZ004777, Tyr312 is rotated away from this channel to accommodate the t-butyl moiety (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…There are 60 PMTs encoded in the human genome, including 51 lysine methyltransferases (PKMTs) and 9 protein arginine methyltransferases (PRMTs) 1 . Most PKMTs contain a conserved SET domain, with the exception of DOT1L, which has a protein fold that more closely resembles PRMTs 6 . DOT1L is also unique in that it is the only PKMT to methylate histone H3 on Lysine 79 (H3K79) 7,8 , a chromatin mark associated with active chromatin and transcriptional elongation 9 .…”

mentioning

confidence: 99%

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Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

et al. 2012

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Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethioninecompetitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy.

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Section: Resultssupporting

confidence: 74%

“…The catalytic subunit of DOT1L comprises its first 416 residues 6 . Mono-and dimethylation of H3K79 is dependent on SAM (Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

et al. 2012

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“…Yeast Dot1p and its human homolog Dot1L methylate only nucleosomal substrates, but not free histone H3 protein [60,[67][68][69]. A stretch of positively charged residues C-terminal to the human Dot1L core or N-terminal to the yeast Dot1p core (Figure 4a) were critical for nucleosome binding and therefore for enzymatic activity [76,77].…”

Section: Dot1p: Non-set Domain Hkmtmentioning

confidence: 99%

Structural dynamics of protein lysine methylation and demethylation

Cheng

Zhang

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Lysine methylation plays a central role in the "histone code" that regulates chromatin structure, impacts transcription, and responds to DNA damage. A single lysine can be mono-, di-, trimethylated, or unmethylated, with different functional consequences for each of the four forms. This review describes structural aspects of methylation of histone lysine residues by two enzyme families with entirely different structural scaffolding (the SET proteins and Dot1p), and the protein motifs that recognize (decode) these methyl-lysine signals. We also discuss the recently discovered protein lysine de-methylating enzymes (LSD1 and JmjC domains). Keywordsprotein lysine methylation and demethylation; SET domain proteins; S-adenosyl-L-methionine (AdoMet)

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Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer

et al. 2019

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Forkhead box transcription factor M1 ( FOXM 1) is a proliferation‐associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells ( DC s). Although previous work has shown that FOXM 1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM 1 affects DC maturation in the context of tumor‐specific immunity. In this study, we examined the central role of FOXM 1 in regulating bone marrow‐derived dendritic cell ( BMDC ) maturation phenotypes and function in pancreatic cancer and colon cancer. FOXM 1 retarded maturation phenotypes of BMDC s, inhibited promotion of T‐cell proliferation, and decreased interleukin‐12 ( IL ‐12) p70 in tumor‐bearing mice ( TBM ). Notably, FOXM 1 expression was epigenetically regulated by dimethylation on H3 lysine 79 (H3K79me2), a modification present in both tumor cells and BMDC s. Increased H3K79me2 enrichment was observed at the FOXM 1 promoter in both BMDC s from TBM , and in BMDC s from wild‐type mice cultured with tumor‐conditioned medium that mimics the tumor microenvironment ( TME ). Furthermore, inhibition of the H3K79 methyltransferase DOT 1L not only decreased enrichment of H3K79me2, but also downregulated expression of FOXM 1 and partially reversed its immunosuppressive effects on BMDC s. Furthermore, we found that FOXM 1 upregulated transcription of Wnt family number 5A (Wnt5a) in BMDC s in vitro ; we also observed that exogenous Wnt5a expression abrogated BMDC maturation phenotypes by inhibiting FOXM 1 and H3K79me2 modification. Therefore, our results reveal that upregulation of FOXM 1 by H3K79me2 in pancreatic cancer and colon cancer significantly inhibits maturation phenotypes and function of BMDC s through the Wnt5a signaling pathway, and thus provide novel insights into FOXM 1‐based antitumor immunotherapy.

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Structure of the Catalytic Domain of Human DOT1L, a Non-SET Domain Nucleosomal Histone Methyltransferase

Cited by 368 publications

References 42 publications

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Structural dynamics of protein lysine methylation and demethylation

Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer

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