Histone H2A Ubiquitination Inhibits the Enzymatic Activity of H3 Lysine 36 Methyltransferases

Yuan, Gang; Ma, Ben; Wen, Yan; Zhang, Zhuqiang; Chen, Ping; Ding, Xiaojun; Li, Feng; Shen, Xiaohua; Chen, She; Li, Guohong; Zhu, Bing

doi:10.1074/jbc.m113.475996

Cited by 53 publications

(45 citation statements)

References 69 publications

(47 reference statements)

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“…As a methyltransferase, Ash1l is able to methylate histone H3K361827, which has been shown in stem cells to be able to antagonize H3K27 tri-methylation, an reaction that is implemented by Polycomb group (PcG) proteins142728. On the other hand, H3K27 tri-methylation is known to be a critical step for PcG dependent activation of c-Myc in tumor cells29.…”

Section: Resultsmentioning

confidence: 99%

The Histone Methyltransferase Ash1l is Required for Epidermal Homeostasis in Mice

Shi

et al. 2017

Sci Rep

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Epidermal homeostasis under normal and healing conditions are critical for the physical and functional maintenance of the skin barrier. It requires a proper balance between keratinocyte proliferation and differentiation under genetic and epigenetic regulations. Here we show that mice carrying a hypomorphic mutation of the histone methyltransferase Ash1l [(absent, small, or homeotic)-like (Drosophila)] develop epidermal hyperplasia and impaired epidermal stratification upon aging. In adult mutants, loss of Ash1l leads to more proliferative keratinocytes in disturbed differentiation stages. After wounding, Ash1l mutation leads to delayed re-epithlialization but increased keratinocyte proliferation at the wound edge. Elevated c-Myc expression could be observed in both aged and wounded mutant tissues. Taken together, these observations revealed an important role of the epigenetic regulator Ash1l in epidermal homeostasis.

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Section: Resultsmentioning

confidence: 99%

The Histone Methyltransferase Ash1l is Required for Epidermal Homeostasis in Mice

Shi

et al. 2017

Sci Rep

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“…Moreover, we did not detect an increase in H3K36me3 despite the proposed antagonistic relationship between H2AK119ub and H3K36me2/3 deposition ( Fig. 1D; Yuan et al 2013).…”

Section: Ring1b Catalytic Activity Is Dispensable For Repression At Mmentioning

confidence: 85%

The E3 ubiquitin ligase activity of RING1B is not essential for early mouse development

et al. 2015

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Polycomb-repressive complex 1 (PRC1) and PRC2 maintain repression at many developmental genes in mouse embryonic stem cells and are required for early development. However, it is still unclear how they are targeted and how they function. We show that the ability of RING1B, a core component of PRC1, to ubiquitinate histone H2A is dispensable for early mouse embryonic development and much of the gene repression activity of PRC1. Our data support a model in which PRC1 and PRC2 reinforce each other's binding but suggest that the key functions of PRC1 lie beyond the enzymatic capabilities of RING1B.

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“…In fact, H3K36 premethylation inhibits PRC2 H3K27-KMTase activity in in vitro assays [37]. Conversely, H3K36 KMTases are inhibited by ubiquitinated H2A, a mark made by polycomb repressive complex 1 [38]. As development proceeds, however, the PRC2 complex must invade active, H3K36-methylated chromatin to silence certain genes.…”

Section: Dna Repairmentioning

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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Histone H2A Ubiquitination Inhibits the Enzymatic Activity of H3 Lysine 36 Methyltransferases

Cited by 53 publications

References 69 publications

The Histone Methyltransferase Ash1l is Required for Epidermal Homeostasis in Mice

The Histone Methyltransferase Ash1l is Required for Epidermal Homeostasis in Mice

The E3 ubiquitin ligase activity of RING1B is not essential for early mouse development

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

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