Cancers and the NSD family of histone lysine methyltransferases

Morishita, Masaki; Luccio, Eric di

doi:10.1016/j.bbcan.2011.05.004

Cited by 82 publications

(158 citation statements)

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“…Deletion of the gene encoding the histone H3K36 dimethyltransferase enzyme nuclear receptor binding SET domain protein 2 (NSD2) (also known as WHSC1 or MMSET), specifically, is present in the developmental disorder Wolf-Hirschhorn syndrome (9). 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).…”

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confidence: 99%

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: 99%

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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“…In contrast, the specific molecular functions associated with H3K36me2 are unclear. However, elevated levels of this modification lead to aberrant activation of normally silenced genes (11), and up-regulation of this mark is linked with numerous cancer types including acute myeloid leukemia, multiple myeloma, lung cancers, breast cancers, and glioblastomas (11)(12)(13)(14). Thus, different states of methylation at H3K36 (dimethyl versus trimethyl) are linked to dramatically different biological and disease-associated readouts.…”

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confidence: 99%

A PWWP Domain of Histone-Lysine N-Methyltransferase NSD2 Binds to Dimethylated Lys-36 of Histone H3 and Regulates NSD2 Function at Chromatin

Sankaran¹,

Wilkinson²,

Elias

et al. 2016

Journal of Biological Chemistry

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The readout of histone modifications plays a critical role in chromatin-regulated processes. Dimethylation at Lys-36 on histone H3 (H3K36me2) is associated with actively transcribed genes, and global up-regulation of this modification is associated with several cancers. However, the molecular mechanism by which H3K36me2 is sensed and transduced to downstream biological outcomes remains unclear. Here we identify a PWWP domain within the histone lysine methyltransferase and oncoprotein NSD2 that preferentially binds to nucleosomes containing H3K36me2. In cells, the NSD2 PWWP domain interaction with H3K36me2 plays a role in stabilizing NSD2 at chromatin. Furthermore, NSD2's ability to induce global increases in H3K36me2 via its enzymatic activity, and consequently promote cellular proliferation, is compromised by mutations within the PWWP domain that specifically abrogate H3K36me2-recognition. Together, our results identify a pivotal role for NSD2 binding to its catalytic product in regulating its cellular functions, and suggest a model for how this interaction may facilitate epigenetic spreading and propagation of H3K36me2.Chromatin dynamics play a critical role in the regulation of diverse cellular functions, the dysregulation of which is linked to the development and progression of human diseases. A major mechanism for regulating chromatin functional states involves the reversible covalent post-translational modification of histone proteins by chemical moieties such as methyl-, acetyl-, and phospho-groups. Histones provide a highly modifiable signaling surface on which these chemical marks combine to define particular chromatin states and regulate the extent of accessibility of DNA to trans-acting factors. In this context, the proteins and domains that recognize histone modification fundamentally influence DNA-templated processes, transducing molecular events at chromatin to biological outcomes. Protein lysine methylation is a principal chromatin-regulatory mechanism. The chemical addition of methyl moieties to lysine residues is catalyzed by lysine methyltransferases (KMTs).3 Lysine residues can accept up to three methyl groups forming mono-, di-, and tri-methylated derivatives (referred to as me1, me2, and me3, respectively). Histone methylation has been linked via methyllysine-binding proteins to diverse processes, including transcription, DNA recombination, DNA repair, and DNA replication.Methylation of histone H3 at lysine 36 (H3K36) is found at gene bodies of actively transcribed genes, but the state of methylation at this residue defines distinct biological outcomes. Trimethylation of this site (H3K36me3), which is mediated by the KMT SETD2 in humans, is involved in splicing regulation, RNA processing, and DNA damage signaling (1-7). Loss of SETD2 and H3K36me3 is a recurring phenomenon in clear cell renal cell carcinoma (ccRCC) and other cancers, suggesting a tumor suppressor role for SETD2 (8 -10). In contrast, the specific molecular functions associated with H3K36me2 are unclear. However, elevated level...

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“…The amplification of either NSD1 or NSD2 triggers cellular transformation [21][22][23][24][25][26][27][28]. NSD2 is associated with tumor aggressiveness or prognosis in most types of cancers, including prostate cancer and multiple myeloma and is overexpressed in at least 15 different cancers [9,10,17,18,20,21,25,[29][30][31][32][33]. Increased NSD2 activity is also reported during tumor proliferation in glioblastoma and myeloma [34], resulting in aberrantly high global levels of H3K36me2 [18].…”

Section: Introductionmentioning

confidence: 99%

“…The NSD proteins are oncogenes highly expressed in numerous pathological conditions and are considered attractive novel therapeutic targets in cancers [2,[9][10][11][12][13][14][15][16][17][18][19][20]. The amplification of NSD1 has been reported in multiple myeloma, lung cancer, neuroblastoma and glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

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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Cancers and the NSD family of histone lysine methyltransferases

Cited by 82 publications

References 52 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

A PWWP Domain of Histone-Lysine N-Methyltransferase NSD2 Binds to Dimethylated Lys-36 of Histone H3 and Regulates NSD2 Function at Chromatin

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

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