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

Morishita, Masaki; Mevius, Damiaan E. H. F.; Luccio, Eric di

doi:10.1186/s12900-014-0025-x

Cited by 39 publications

(28 citation statements)

References 57 publications

(96 reference statements)

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“…KIEs measured for the atomic positions surrounding the methyl-transfer reaction coordinate are summarized in Table S2 A large primary 14 C KIE is consistent with an S N 2 mechanism where the CH 3 -transfer is largely rate limiting. The magnitude of the primary KIE of the transferring methyl group for S N 2 reaction mechanisms is proportional to the symmetry of the TS structure, with the largest isotope effects expected when bond order to the nucleophile and leaving group are equal (28 (29).…”

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confidence: 65%

“…By contrast, NSD2 overexpression, as a result of a t(4;14) chromosomal translocation (10), is manifest in 15% of multiple myeloma cases and has been identified in other cancers (11)(12)(13). NSD2 catalyzes the monomethylation and dimethylation of histone H3K36 in vivo (11), although other CH 3 -transfer specificities have also been reported in studies using histone protein or histone tail peptide as substrate analogs (14)(15)(16). Studies using isolated or recombinant nucleosome as physiologically relevant substrates detected H3K36Me1 and H3K36Me2 as the exclusive products.…”

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confidence: 99%

“…To assess the possibility that QM tunneling contributes to our observed Me-14 C KIE, we calculated predicted Me- 14 C KIEs while including a correction for carbon tunneling. For our system, the magnitude of predicted KIEs including tunneling are larger than the intrinsic value for all TS geometries tested (Fig.…”

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confidence: 99%

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Transition state for the NSD2-catalyzed methylation of histone H3 lysine 36

Poulin

Schneck

Matico

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear receptor SET domain containing protein 2 (NSD2) catalyzes the methylation of histone H3 lysine 36 (H3K36). It is a determinant in Wolf-Hirschhorn syndrome and is overexpressed in human multiple myeloma. Despite the relevance of NSD2 to cancer, there are no potent, selective inhibitors of this enzyme reported. Here, a combination of kinetic isotope effect measurements and quantum chemical modeling was used to provide subangstrom details of the transition state structure for NSD2 enzymatic activity. Kinetic isotope effects were measured for the methylation of isolated HeLa cell nucleosomes by NSD2. NSD2 preferentially catalyzes the dimethylation of H3K36 along with a reduced preference for H3K36 monomethylation. Primary Me- H 2 kinetic isotope effects were measured for the methylation of H3K36 using specifically labeled S-adenosyl-L-methionine. The intrinsic kinetic isotope effects were used as boundary constraints for quantum mechanical calculations for the NSD2 transition state. The experimental and calculated kinetic isotope effects are consistent with an S N 2 chemical mechanism with methyl transfer as the first irreversible chemical step in the reaction mechanism. The transition state is a late, asymmetric nucleophilic displacement with bond separation from the leaving group at (2.53 Å) and bond making to the attacking nucleophile (2.10 Å) advanced at the transition state. The transition state structure can be represented in a molecular electrostatic potential map to guide the design of inhibitors that mimic the transition state geometry and charge.enzyme mechanism | transition state structure | histone methylation | kinetic isotope effects

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confidence: 65%

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confidence: 99%

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Transition state for the NSD2-catalyzed methylation of histone H3 lysine 36

Poulin

Schneck

Matico

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…1c, d). NSD2 may also function as histone H3K79 methyltransferase in the cerebellum [37]. However, Nsd2 transcription did not change upon Dot1l -cKO Atoh1 (Fig.…”

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confidence: 99%

Differential Methylation of H3K79 Reveals DOT1L Target Genes and Function in the Cerebellum In Vivo

et al. 2018

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The disruptor of telomeric silencing 1-like (DOT1L) mediates methylation of histone H3 at position lysine 79 (H3K79). Conditional knockout of Dot1l in mouse cerebellar granule cells ( Dot1l -cKO Atoh1 ) led to a smaller external granular layer with fewer precursors of granule neurons. Dot1l -cKO Atoh1 mice had impaired proliferation and differentiation of granular progenitors, which resulted in a smaller cerebellum. Mutant mice showed mild ataxia in motor behavior tests. In contrast, Purkinje cell-specific conditional knockout mice showed no obvious phenotype. Genome-wide transcription analysis of Dot1l -cKO Atoh1 cerebella using microarrays revealed changes in genes that function in cell cycle, cell migration, axon guidance, and metabolism. To identify direct DOT1L target genes, we used genome-wide profiling of H3K79me2 and transcriptional analysis. Analysis of differentially methylated regions (DR) and differentially expressed genes (DE) revealed in total 12 putative DOT1L target genes in Dot1l -cKO Atoh1 affecting signaling ( Tnfaip8l3, B3galt5 ), transcription ( Otx1 ), cell migration and axon guidance ( Sema4a , Sema5a , Robo1 ), cholesterol and lipid metabolism ( Lss , Cyp51 ), cell cycle ( Cdkn1a ), calcium-dependent cell-adhesion or exocytosis ( Pcdh17 , Cadps2 ), and unknown function ( Fam174b ). Dysregulated expression of these target genes might be implicated in the ataxia phenotype observed in Dot1l -cKO Atoh1 . Electronic supplementary material The online version of this article (10.1007/s12035-018-1377-1) contains supplementary material, which is available to authorized users.

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“…The substrate specificity of NSD2, while most likely being the Lys36 of histone H3 in vivo , remains somewhat controversial and in vitro depends on the nature of a substrate [19,20]. The methylation of Lys36 of histone H3 has been implicated in the process of RNA elongation during transcription, thus suggesting that NSD2 contributes to the generation of full‐length transcripts [21].…”

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confidence: 99%

The catalytic domain of the histone methyltransferase NSD2/MMSET is required for the generation of B1 cells in mice

et al. 2020

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Edited by Wilfried Ellmeier Humoral immunity in mammals relies on the function of two developmentally and functionally distinct B-cell subsets-B1 and B2 cells. While B2 cells are responsible for the adaptive response to environmental antigens, B1 cells regulate the production of polyreactive and low-affinity antibodies for innate humoral immunity. The molecular mechanism of B-cell specification into different subsets is understudied. In this study, we identified lysine methyltransferase NSD2 (MMSET/WHSC1) as a critical regulator of B1 cell development. In contrast to its minor impact on B2 cells, deletion of the catalytic domain of NSD2 in primary B cells impairs the generation of B1 lineage. Thus, NSD2, a histone H3 K36 dimethylase, is the first-in-class epigenetic regulator of a B-cell lineage in mice.

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

Cited by 39 publications

References 57 publications

Transition state for the NSD2-catalyzed methylation of histone H3 lysine 36

Transition state for the NSD2-catalyzed methylation of histone H3 lysine 36

Differential Methylation of H3K79 Reveals DOT1L Target Genes and Function in the Cerebellum In Vivo

The catalytic domain of the histone methyltransferase NSD2/MMSET is required for the generation of B1 cells in mice

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