Lysine Methylation Regulators Moonlighting outside the Epigenome

Cornett, Evan M.; Ferry, Laure; Defossez, Pierre‐Antoine; Rothbart, Scott B.

doi:10.1016/j.molcel.2019.08.026

Cited by 73 publications

(84 citation statements)

References 85 publications

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“…More recently, it was appreciated that non-histone proteins are also targeted by lysine methylase and demethylase, and that the molecular function of this modification in these targets mirrors what was previously described for histones, representing a signal for association with effector proteins [5]. Overall, the current interpretation is that lysine methylation plays a similar role in histone and nonhistone substrates, modulating protein-protein and protein-DNA interactions [5,6].…”

Section: Lysine Methylation and Cancermentioning

confidence: 69%

SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

Bottino

Peserico

Simone

et al. 2020

Cancers

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SMYD3 is a member of the SMYD lysine methylase family and plays an important role in the methylation of various histone and non-histone targets. Aberrant SMYD3 expression contributes to carcinogenesis and SMYD3 upregulation was proposed as a prognostic marker in various solid cancers. Here we summarize SMYD3-mediated regulatory mechanisms, which are implicated in the pathophysiology of cancer, as drivers of distinct oncogenic pathways. We describe SMYD3-dependent mechanisms affecting cancer progression, highlighting SMYD3 interplay with proteins and RNAs involved in the regulation of cancer cell proliferation, migration and invasion. We also address the effectiveness and mechanisms of action for the currently available SMYD3 inhibitors. The findings analyzed herein demonstrate that a complex network of SMYD3-mediated cytoplasmic and nuclear interactions promote oncogenesis across different cancer types. These evidences depict SMYD3 as a modulator of the transcriptional response and of key signaling pathways, orchestrating multiple oncogenic inputs and ultimately, promoting transcriptional reprogramming and tumor transformation. Further insights into the oncogenic role of SMYD3 and its targeting of different synergistic oncogenic signals may be beneficial for effective cancer treatment.

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Section: Lysine Methylation and Cancermentioning

confidence: 69%

SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

Bottino

Peserico

Simone

et al. 2020

Cancers

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“…The study of Kme reader-protein interactions is expanding beyond histones (Cornett et al, 2019). For example, M-phase phosphoprotein 8 (MPP8) is a Kme reader that, like HP1, was linked to gene silencing through recognition of H3K9me3 through its chromodomain (Kokura et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

A Degenerate Peptide Library Approach to Reveal Sequence Determinants of Methyllysine-Driven Protein Interactions

Kupai

Vaughan

Dickson

et al. 2020

Front. Cell Dev. Biol.

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Lysine methylation facilitates protein-protein interactions through the activity of methyllysine (Kme) "reader" proteins. Functions of Kme readers have historically been studied in the context of histone interactions, where readers aid in chromatin-templated processes such as transcription, DNA replication and repair. However, there is growing evidence that Kme readers also function through interactions with non-histone proteins. To facilitate expanded study of Kme reader activities, we developed a high-throughput binding assay to reveal the sequence determinants of Kme-driven protein interactions. The assay queries a degenerate methylated lysine-oriented peptide library (Kme-OPL) to identify the key residues that modulate reader binding. The assay recapitulated methyl order and amino acid sequence preferences associated with histone Kme readers. The assay also revealed methylated sequences that bound Kme readers with higher affinity than histones. Proteome-wide scoring was applied to assay results to help prioritize future study of Kme reader interactions. The platform was also used to design sequences that directed specificity among closely related reader domains, an application which may have utility in the development of peptidomimetic inhibitors. Furthermore, we used the platform to identify binding determinants of site-specific histone Kme antibodies and surprisingly revealed that only a few amino acids drove epitope recognition. Collectively, these studies introduce and validate a rapid, unbiased, and high-throughput binding assay for Kme readers, and we envision its use as a resource for expanding the study of Kme-driven protein interactions.

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“…Accordingly, we found that G9a interacted with PAX3-FOXO1 in two different FP-RMS cell lines ( Figure 3E), and this interaction was reduced in cells treated with the G9a inhibitor A-366 ( Figure 3F). As G9a has a well-known role in methylating non-histone proteins, and lysine methylation promotes protein stability (25), these results strongly suggest that G9a might stabilize PAX3-FOXO1 through methylation. In further support of this, transcriptomic analysis by RNA-seq revealed that G9a depletion in FP-9 ARMS cells (Supplemental Figure 3B) induced transcriptional changes inversely correlated by those imposed by PAX3-FOXO1 expression (26,27), as revealed by Gene Set Enrichment Analysis (GSEA) ( Figure 3G).…”

Section: G9a Regulates Pax3-foxo1 Protein Stability Thus Sustaining Fmentioning

confidence: 70%

The RNA helicase DDX5 promotes alveolar rhabdomyosarcoma growth and survival

Gualtieri

Licursi

Mozzetta

2020

Preprint

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AbstractRhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood characterized by the inability to exit the proliferative myoblast-like stage. The alveolar fusion positive subtype (FP-ARMS) is the most aggressive and is mainly caused by the expression of PAX3/7-FOXO1 oncoproteins, which are challenging pharmacological targets. Thus, other therapeutic vulnerabilities resulting from gene expression changes are progressively being recognized. Here, we identified the DEAD box RNA helicase 5 (DDX5) as a potential therapeutic target to inhibit FP-ARMS growth. We show that DDX5 is overexpressed in alveolar RMS cells, demonstrating that its depletion drastically decreases FP-ARMS viability and slows tumor growth in xenograft models. Mechanistically, we provide evidence that DDX5 functions upstream the G9a/AKT survival signalling pathway, by modulating G9a protein stability. Finally, we show that G9a interacts with PAX3-FOXO1 and regulates its activity, thus sustaining FP-ARMS myoblastic state. Together, our findings identify a novel survival-promoting loop in FP-ARMS and highlight DDX5 as potential therapeutic target to arrest rhabdomyosarcoma growth.

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Lysine Methylation Regulators Moonlighting outside the Epigenome

Cited by 73 publications

References 85 publications

SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

A Degenerate Peptide Library Approach to Reveal Sequence Determinants of Methyllysine-Driven Protein Interactions

The RNA helicase DDX5 promotes alveolar rhabdomyosarcoma growth and survival

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