Histone demethylase KDM5A is an integral part of the core Notch–RBP-J repressor complex

Liefke, Robert; Oswald, Franz; Alvarado, Cristobal G.; Ferres-Marco, Dolores; Mittler, Gerhard; Rodriguez, Patrick; Domı́nguez, Marı́a; Borggrefe, Tilman

doi:10.1101/gad.563210

Cited by 168 publications

(172 citation statements)

References 51 publications

(63 reference statements)

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“…24 Recently, RBP2 protein was shown to be an integral part of the core Notch-RBP-J repressor complex, contributing to switch off the Notch signaling. 25 In contrast to its tumor suppressor function, Sharma et al have shown the link between RBP2 and drug resistance. 26 RBP2 was elevated in drug-tolerant subpopulation of cancer cells, which were treated with a receptor tyrosine kinase inhibitor and RBP2 knockdown significantly reduced the number of drug tolerant population.…”

Section: Rbp2/jarid1a/kdm5amentioning

confidence: 99%

Epigenetic regulation of cancer growth by histone demethylases

Lim

Metzger

Schüle

et al. 2010

Intl Journal of Cancer

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Cancer is traditionally viewed as a primarily genetic disorder. However, it is now increasingly apparent that epigenetic abnormalities play a fundamental role in cancer development. Aberrant expression of histone-modifying enzymes has been implicated in the course of tumor initiation and progression. The discovery of a large number of histone demethylases suggests an important role for dynamic regulation of histone methylation in biological processes. The observation that overexpression, amplification or mutations of several histone demethylases have been found in many types of tumors, raise the possibility of using these enzymes as diagnostic tools as well as pave a way for the discovery of novel therapeutic targets and treatment modalities. Here, we review the current knowledge of the potential role of H3K4, H3K9 and H3K27 histone demethylases in tumorigenesis.Recently, it has become apparent that not only genetic mutations but also epigenetic alterations lead to the activation of oncogenes and the loss of function of tumor-suppressor genes. Since epigenetic abnormalities in DNA methylation patterns as well as histone modifications are potentially reversible in contrast to gene mutations, much effort has been directed toward understanding the mechanism of epigenetic aberration to develop epigenetic therapies. Indeed, inhibitors of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) have been approved for treatment of certain types of cancers. Recently, overexpression, amplification or mutations of several histone demethylases have been linked to many types of tumor, raising the possibility of using these enzymes as diagnostic tools and therapeutic targets. Here, we focus mainly on the potential role of some selected histone lysine demethylases in tumorigenesis.The N-terminal tails of histones are subjected to several types of post-translational modifications, including acetylation, methylation, phosphorylation and ubiquitination. The combination of these modifications determines chromatin structure and transcriptional activation or repression of genes. In contrast to other histone modifications, the importance of histone methylations is highlighted because of their enormously specific dynamics with respect to gene regulation. Histone lysine residues on histone H3 and H4 (H3K4, H3K9, H3K27, H3K36, H3K79 and H4K20) can become mono-, dior trimethylated. These modifications are regulated by two classes of enzymes with opposing activities: histone methyltransferases and histone lysine demethylases. LSD1, also known as AOF2 and KDM1, is the first discovered histone lysine demethylase that belongs to the flavin adenine dinucleotide-dependent enzyme family. 1 Subsequently, another family of histone lysine demethylases structurally different from LSD1 was described, all of which sharing the conserved jumonji C (JmjC) domain (Table 1). H3K4 Demethylases in Cancer LSD1/KDM1ATri-and dimethylated H3K4 (H3K4me3/2) are often found at actively transcribed genes. Although H3K4me3 is highly enriched around transcrip...

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Section: Rbp2/jarid1a/kdm5amentioning

confidence: 99%

Epigenetic regulation of cancer growth by histone demethylases

Lim

Metzger

Schüle

et al. 2010

Intl Journal of Cancer

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“…However, evidence that invertebrate SHARP and CIR1 proteins mediate substantial aspects of Notch target repression in vivo is limited. Recently, the histone demethylases KDM5A/Lid were reported as conserved members of CBF1-Su(H) co-repressor complexes that bind directly to these transcription factors (Moshkin et al, 2009;Liefke et al, 2010), although these chromatin factors have pleiotropic functions involving diverse DNA-binding partners such as Rb, Myc (also known as Dm in Drosophila) and PRC2 (Polycomb repressive complex 2) (Fattaey et al, 1993;Secombe et al, 2007;Pasini et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

BEND6 is a nuclear antagonist of Notch signaling during self-renewal of neural stem cells

et al. 2013

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SUMMARYThe activity of the Notch pathway revolves around a CSL-class transcription factor, which recruits distinct complexes that activate or repress target gene expression. The co-activator complex is deeply conserved and includes the cleaved Notch intracellular domain (NICD) and Mastermind. By contrast, numerous CSL co-repressor proteins have been identified, and these are mostly different between invertebrate and vertebrate systems. In this study, we demonstrate that mammalian BEND6 is a neural BEN-solo factor that shares many functional attributes with Drosophila Insensitive, a co-repressor for the Drosophila CSL factor. BEND6 binds the mammalian CSL protein CBF1 and antagonizes Notch-dependent target activation. In addition, its association with Notch-and CBF1-regulated enhancers is promoted by CBF1 and antagonized by activated Notch. In utero electroporation experiments showed that ectopic BEND6 inhibited Notch-mediated self-renewal of neocortical neural stem cells and promoted neurogenesis. Conversely, knockdown of BEND6 increased NSC self-renewal in wild-type neocortex, and exhibited genetic interactions with gain and loss of Notch pathway activity. We recapitulated all of these findings in cultured neurospheres, in which overexpression and depletion of BEND6 caused reciprocal effects on neural stem cell renewal and neurogenesis. These data reveal a novel mammalian CSL co-repressor in the nervous system, and show that the Notch-inhibitory activity of certain BEN-solo proteins is conserved between flies and mammals.

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“…Domains selected for analysis include fragments responsible for DNA interactions; specifically, the β-hairpin which, in the case of PHD domains, is characterized by the stabilizing presence of zinc (Zn 2+ ) ions. Our selection is motivated by the fact that these domains participate in epigenetic phenomena (histone demethylase activity) [18] as well as in polycomb complexation [19][20][21], both of which are important in the context of pathological (disease-related) processes [22,23].…”

Section: Introductionmentioning

confidence: 99%

Application of Divergence Entropy to Characterize the Structure of the Hydrophobic Core in DNA Interacting Proteins

Kalinowska

Banach

Konieczny

et al. 2015

Entropy

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Abstract:The fuzzy oil drop model, a tool which can be used to study the structure of the hydrophobic core in proteins, has been applied in the analysis of proteins belonging to the jumonji group-JARID2, JARID1A, JARID1B and JARID1D-proteins that share the property of being able to interact with DNA. Their ARID and PHD domains, when analyzed in the context of the fuzzy oil drop model, are found to exhibit structural variability regarding the status of their secondary folds, including the β-hairpin which determines their biological function. Additionally, the structure of disordered fragments which are present in jumonji proteins (as confirmed by the DisProt database) is explained on the grounds of the hydrophobic core model, suggesting that such fragments contribute to tertiary structural stabilization. This conclusion is supported by divergence entropy measurements, expressing the degree of ordering in each protein's hydrophobic core.

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Histone demethylase KDM5A is an integral part of the core Notch–RBP-J repressor complex

Cited by 168 publications

References 51 publications

Epigenetic regulation of cancer growth by histone demethylases

Epigenetic regulation of cancer growth by histone demethylases

BEND6 is a nuclear antagonist of Notch signaling during self-renewal of neural stem cells

Application of Divergence Entropy to Characterize the Structure of the Hydrophobic Core in DNA Interacting Proteins

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