Structural Insights into Estrogen Receptor α Methylation by Histone Methyltransferase SMYD2, a Cellular Event Implicated in Estrogen Signaling Regulation

Jiang, Yuanyuan; Trescott, Laura; Holcomb, Joshua; Zhang, Xi; Brunzelle, J.S.; Sirinupong, Nualpun; Shi, Xiaobing; Yang, Zhe

doi:10.1016/j.jmb.2014.02.019

Cited by 53 publications

(61 citation statements)

References 50 publications

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“…The p53 and ER-α peptides bind in a U-shaped conformation at the hinge region between the N-and C-terminal lobes, with the target lysine at the base of the 'U' [123,124,132]. The target lysine projects deep into a hydrophobic cavity, with the lysine ε-amino group oriented by the hydroxyl groups of two conserved tyrosine residues and several main chain carbonyl groups.…”

Section: Structural Studies Of Nsd Ash1l and Setd2 Set Domains Demonstmentioning

confidence: 99%

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors. Nevertheless, potent inhibitors for most H3K36 KMTases have not yet been developed, underlining the challenges associated with this target class. As we now have strong evidence linking H3K36 KMTases to cancer, drug development efforts are predicted to yield novel compounds in the near future. Cellular development and differentiation are controlled by post-translational modifications on DNA and histone proteins, forming an epigenetic (above the genes) regulatory network. Disruption of epigenetic pathways is a nearly universal feature of cancer, causing aberrations in gene expression and genome integrity (reviewed in [1]). A key group of epigenetic enzymes disrupted in cancer is the lysine methyltransferases (KMTases), which install methyl groups on histone proteins. In cancer cells, methylation performed by KMTases drives proliferation and halts differentiation by modifying gene transcription and other DNA-templated processes [2][3][4]. Over the past decade, KMTases have emerged as important drug targets for both industrial and academic research groups. Some progress has been made, most notably by selective inhibitors for the EZH2 and DOT1L KMTases that have reached clinical trials for the treatment of nonHodgkin lymphoma and acute leukemia, respectively [5,6]. Nevertheless, selective and cell permeable inhibitors for many KMTases remain unavailable.Methylation at H3K36 represents a particularly important chromatin mark implicated in diverse forms of cancer. KMTases with specificity toward H3K36 are overexpressed in cancer cells and have been characterized as regulators of cell growth, differentiation, stemness and DNA repair pathways [7][8][9]. However, very few selective and cell-active small molecule inhibitors of H3K36-specfic KMTases have been reported to date. In this article, we provide an overview of cellular pathways involving H3K36 methylation and discuss the diverse functions carried out by the eight different human H3K36-specific KMTases. Then we analyze structural characteristics of the catalytic SET domain of H3K36 KMTases and evaluate prospects for their inhibition by small molecules. Review Rogawski, Grembecka & Cierpicki We conclude with a discussion of the challenges and o pportunities for targeting these proteins. SPECIAL FOCUS y Epigenetic drug discovery H3K36 methylation regulates diverse processes implicated in cancerH3K36 methylation participates in a wide variety of nuclear pathways. Many of these processes, including transcriptional regulation, alternative spli...

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Section: Structural Studies Of Nsd Ash1l and Setd2 Set Domains Demonstmentioning

confidence: 99%

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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“…Further, SMYD2 inhibits p53 function by methylating lysine 370 (K370) (Huang et al, 2006). In addition, SMYD2 methylates K810 and K860 of the retinoblastoma (RB) tumor suppressor, as well as the estrogen receptor α (ERα), poly(ADP-ribose) polymerase 1 (PARP1), and HSP90 (Cho et al, 2012, Saddic et al, 2010, Jiang et al, 2014, Zhang et al, 2013, Piao et al, 2014, Abu-Farha et al, 2011). And recently, BTF3, PDAP1, AHNAK, and AHNAK2 were identified to be methylated by SMYD2 (Olsen et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency

Boehm

Jeng

Camus

et al. 2017

Cell Host & Microbe

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Summary Transcriptional latency of HIV is a last barrier to viral eradication. Chromatin-remodeling complexes and post-translational histone modifications likely play key roles in HIV-1 reactivation but the underlying mechanisms are incompletely understood. We performed a RNAi-based screen of human lysine methyltransferases and identified the SET and MYND domain-containing protein 2 (SMYD2) as an enzyme that regulates HIV-1 latency. Knockdown of SMYD2 or its pharmacological inhibition reactivated latent HIV-1 in T-cell lines and in primary CD4+ T cells. SMYD2 associated with latent HIV-1 promoter chromatin, which was enriched in monomethylated lysine 20 at histone H4 (H4K20me1), a mark lost in cells lacking SMYD2. Further, we find that lethal 3 malignant brain tumor 1 (L3MBTL1), a reader protein with chromatin-compacting properties that recognizes H4K20me1, was recruited to the latent HIV-1 promoter in a SMYD2-dependent manner. We propose that a SMYD2-H4K20me1-L3MBTL1 axis contributes to HIV-1 latency and can be targeted with small-molecule SMYD2 inhibitors.

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“…The preference of SMYD2 for leucine and phenylalanine at the −1 site of the target peptide can be explained by the structure of the enzyme in complex with the p53 (PDB ID: 3S7F) or ERα peptides (PDB ID: 4O6F). In both structures, the corresponding target peptide leucine residue at the −1 site is in close proximity to methyl groups of SMYD2 residues T105, L108, V179, and T185 and further contacted by the Cα of N180 and G183 and Cβ of S196, altogether creating a hydrophobic pocket large enough to accommodate a leucine residue (Figure A). The disfavor for acidic residues at the +1 to +3 sites in the target peptide can be explained by the close proximity of two acidic side chains from SMYD2 (E187 and D242) and the general acidic nature of the peptide binding pocket (Figure B).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, SMYD2 also methylates the estrogen receptor alpha (ERα) protein at lysine 266 repressing ERα transactivation activity . Details of the substrate peptide recognition of SMYD2 have been identified by two structures of the enzyme with the p53 and the ERα peptide substrates . In addition, several other non‐histone targets were identified in the last couple of years, including PARP1, MAPKAPK3 and PTEN .…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Substrate Specificity of the SMYD2 Protein Lysine Methyltransferase and Discovery of Novel Non‐Histone Substrates

et al. 2019

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The SMYD2 protein lysine methyltransferase methylates various histone and non‐histone proteins and is overexpressed in several cancers. Using peptide arrays, we investigated the substrate specificity of the enzyme, revealing a recognition of leucine (or weaker phenylalanine) at the −1 peptide site and disfavor of acidic residues at the +1 to +3 sites. Using this motif, novel SMYD2 peptide substrates were identified, leading to the discovery of 32 novel peptide substrates with a validated target site. Among them, 19 were previously reported to be methylated at the target lysine in human cells, strongly suggesting that SMYD2 is the protein lysine methyltransferase responsible for this activity. Methylation of some of the novel peptide substrates was tested at the protein level, leading to the identification of 14 novel protein substrates of SMYD2, six of which were more strongly methylated than p53, the best SMYD2 substrate described so far. The novel SMYD2 substrate proteins are involved in diverse biological processes such as chromatin regulation, transcription, and intracellular signaling. The results of our study provide a fundament for future investigations into the role of this important enzyme in normal development and cancer.

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Structural Insights into Estrogen Receptor α Methylation by Histone Methyltransferase SMYD2, a Cellular Event Implicated in Estrogen Signaling Regulation

Cited by 53 publications

References 50 publications

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency

Analysis of the Substrate Specificity of the SMYD2 Protein Lysine Methyltransferase and Discovery of Novel Non‐Histone Substrates

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