Structural insights into the regulation and the recognition of histone marks by the SET domain of NSD1

Morishita, Masaki; Luccio, Eric di

doi:10.1016/j.bbrc.2011.07.061

Cited by 28 publications

(51 citation statements)

References 33 publications

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“…and translated~6 ? at the tip, which is a significant displacement (Figure 3) [9]. The rest of the backbone did not undergo significant structural modifications, with an overall c α -RMSD < 0.6 ?…”

Section: Molecular Modelling and The Open-and-closed Conformation Of mentioning

confidence: 94%

“…To gain further insight into histone lysine methylation by the NSD members, we investigated conformational modifications of the catalytic domain (CD) to gain access to the lysine-binding pocket. The crystal structure of NSD1-CD (PDB: 3OOI) is devoid of substrate and the histone-lysine binding area is occluded by a regulatory loop at the interface of the SET and post-SET regions (Figure 3) [9,51]. Previously, we showed that molecular determinants of this regulatory loop extend over the histone-binding site, sterically preventing substrates from binding [51][52][53].…”

Section: Molecular Modelling and The Open-and-closed Conformation Of mentioning

confidence: 99%

“…Longrange MD simulations were applied to allow complexes to equilibrate into stable conformations with little RMSD oscillations observed for the post-SET regions (overall c α -RMSD < 0.6 ? ) [9]. The resulting models may approximate the conformations of the opened CD potentially resulting from the binding of nucleosomal DNA as an allosteric effector.…”

Section: Molecular Modelling and The Open-and-closed Conformation Of mentioning

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%

“…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%

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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: Molecular Modelling and The Open-and-closed Conformation Of mentioning

confidence: 94%

Section: Molecular Modelling and The Open-and-closed Conformation Of mentioning

confidence: 99%

Section: Molecular Modelling and The Open-and-closed Conformation Of mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Morishita

Mevius

Luccio

2014

BMC Structural Biology

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The histone methyltransferase Wolf–Hirschhorn syndrome candidate 1‐like 1 (WHSC1L1) is involved in human carcinogenesis

Kang

Cho

Toyokawa

et al. 2012

Genes Chromosomes & Cancer

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Histone lysine methylation plays a fundamental role in chromatin organization. Although a set of histone methyltransferases have been identified and biochemically characterized, the pathological roles of their dysfunction in human cancers are still not well understood. In this study, we demonstrate important roles of WHSC1L1 in human carcinogenesis. Expression levels of WHSC1L1 transcript were significantly elevated in various human cancers including bladder carcinoma. Immunohistochemical analysis of bladder, lung, and liver cancers confirmed overexpression of WHSC1L1. WHSC1L1-specific small interfering RNAs significantly knocked down its expression and resulted in suppression of proliferation of bladder and lung cancer cell lines. WHSC1L1 knockdown induced cell cycle arrest at the G(2)/M phase followed by multinucleation of cancer cells. Expression profile analysis using Affymetrix GeneChip(®) showed that WHSC1L1 affected the expression of a number of genes including CCNG1 and NEK7, which are known to play crucial roles in the cell cycle progression at mitosis. As WHSC1L1 expression is significantly low in various normal tissues including vital organs, WHSC1L1 could be a good candidate molecule for development of novel treatment for various types of cancer.

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Molecular Dynamics Simulations of Bromodomains Reveal Binding‐Site Flexibility and Multiple Binding Modes of the Natural Ligand Acetyl‐Lysine

Spiliotopoulos

Caflisch

2014

Israel Journal of Chemistry

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Experimental protein structures provide spatial information at the atomic level. A further dimension, time, is supplemented by molecular dynamics. Since the pioneering work on the 58‐residue inhibitor of bovine pancreatic trypsin in the group of Martin Karplus in the seventies, molecular dynamics simulations have shown that the intrinsic flexibility of proteins is essential for their function. Here, we review simulation studies of bromodomains. These protein modules are involved in the recognition of acetylated lysine side chains, a post‐translational modification frequently observed in histone tails. The molecular dynamics simulations have unmasked: (i) the large plasticity of the loops lining the acetyl‐lysine binding site (coupled to its self‐occlusion), and (ii) multiple binding modes of acetyl‐lysine. These simulation results suggest that recognition of histone tails by bromodomains is modulated by their intrinsic flexibility, and further corroborate the utility of molecular dynamics in understanding (macro)molecular recognition.

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Structural insights into the regulation and the recognition of histone marks by the SET domain of NSD1

Cited by 28 publications

References 33 publications

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

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

The histone methyltransferase Wolf–Hirschhorn syndrome candidate 1‐like 1 (WHSC1L1) is involved in human carcinogenesis

Molecular Dynamics Simulations of Bromodomains Reveal Binding‐Site Flexibility and Multiple Binding Modes of the Natural Ligand Acetyl‐Lysine

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