Stable Histone Deacetylase Complexes Distinguished by the Presence of SANT Domain Proteins CoREST/kiaa0071 and Mta-L1

Humphrey, Glen; Wang, Yonghong; Russanova, Valya R.; Hirai, Tazuko H.; Qin, Jun; Nakatani, Yoshihiro; Howard, Bruce H.

doi:10.1074/jbc.m007372200

Cited by 287 publications

(241 citation statements)

References 52 publications

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“…The LSD1/Aof2-Ring1B/Rnf2 complex(es) remain to be characterized fully, but preliminary evidence suggests it is a new entity not identified previously perhaps because it contains a relatively small fraction of Ring1B/Rnf2 (and most likely LSD1/ Aof2 too) in the cell. In fact, this histone demethylase has been identified in a variety of subsets of the Braf-HDAC (BHC) repressing complexes (55)(56)(57)(58), but our analysis of Ring1B/ Rnf2 complexes did not detect either Braf35 or BHC80, two of the components of core BHC complexes (55,58). Thus, our data suggest that the LSD1/Aof2-Ring1B/Rnf2 complex is a novel complex not related to BHC.…”

Section: Discussionmentioning

confidence: 47%

Proteomics Analysis of Ring1B/Rnf2 Interactors Identifies a Novel Complex with the Fbxl10/Jhdm1B Histone Demethylase and the Bcl6 Interacting Corepressor

Sánchez

Demmers³

et al. 2007

Molecular & Cellular Proteomics

209

192

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Ring1B/Rnf2 is a RING finger protein member of the Polycomb group (PcG) of proteins, which form chromatinmodifying complexes essential for embryonic development and stem cell renewal and which are commonly deregulated in cancer. Ring1B/Rnf2 is a ubiquitin E3 ligase that catalyzes the monoubiquitylation of the histone H2A, one of the histone modifications needed for the transcriptional repression activity of the PcG of proteins. Ring1B/Rnf2 was shown to be part of two complexes, the PRC1 PcG complex and the E2F6.com-1 complex, which also contains non-PcG members, thus raising the prospect for additional Ring1B/Rnf2 partners and functions extending beyond the PcG. Here we used a high throughput proteomics approach based on the single step purification, using streptavidin beads, of in vivo biotinylated Ring1B/Rnf2 and associated proteins from a nuclear extract from erythroid cells and their identification by mass spectrometry. About 50 proteins were confidently identified of which 20 had not been identified previously as subunits of Ring1B/Rnf2 complexes. We found that histone demethylases LSD1/Aof2 and Fbxl10/Jhdm1B, casein kinase subunits, and the BcoR corepressor were among the new interactors identified. We also isolated an Fbxl10/Jhdm1B complex by biotinylation tagging to identify shared interacting partners with Ring1B/Rnf2. In this way we identified a novel Ring1B-Fbxl10 complex that also includes Bcl6 corepressor (BcoR), CK2␣, Skp1, and Nspc1/Pcgf1. The putative enzymatic activities and protein interaction and chromatin binding motifs present in this novel Ring1B-Fbxl10 complex potentially provide additional mechanisms for chromatin modification/recruitment to chromatin and more evidence for Ring1B/Rnf2 activities beyond those typically associated with PcG function. Lastly this work demonstrates the utility of biotinylation tagging for the rapid characterization of complex mixtures of multiprotein complexes achieved through the iterative use of this simple yet high throughput proteomics approach.Molecular & Cellular Proteomics 6:820 -834, 2007.In multicellular organisms, cell identity is controlled, at least in part, by epigenetic events, including DNA methylation and post-translational modifications of histones that lead to chromatin structure regulation (1). These modifications are carried out by protein complexes recruited through DNA sequences and/or specific recognition of modified histones. The Polycomb group (PcG) 1 of proteins, first identified genetically as regulators of Hox genes in the fly Drosophila melanogaster (for a review, see Ref. 2), is an example of such a complex. PcG functions cover many aspects of vertebrate development and tissue homeostasis by preventing the inappropriate activation of many transcription factor-coding genes and other genes involved in cell signaling and cell proliferation (3-7). Currently it is believed that PcG proteins play a role in setting the balance between proliferation and differentiation in normal development. Deregulation of PcG proteins disrupts such a ba...

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Section: Discussionmentioning

confidence: 47%

Proteomics Analysis of Ring1B/Rnf2 Interactors Identifies a Novel Complex with the Fbxl10/Jhdm1B Histone Demethylase and the Bcl6 Interacting Corepressor

Sánchez

Demmers³

et al. 2007

Molecular & Cellular Proteomics

209

192

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“…HDAC1 and HDAC2 are mainly found associated in the same molecular complexes with Mi2/ NURD (nucleosome remodelling and histone deacetylase), SIN3A and Co-REST, whereas HDAC3 is found in a different complex (the nuclear co-receptor (NCOR)/ silencing mediator for retinoid and thyroid hormone receptors (SMRT) complex) [126][127][128][129][130][131][132][133] . HDAC6 has been found in cytoplasmic complexes with proteins involved in the ubiquitin signalling pathway 134 .…”

Section: Box 1 | Histone Deacetylase Complexesmentioning

confidence: 99%

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006

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| Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.Histone deacetylases (HDACs) have been intensively scrutinized over the past few years for two main reasons. First, they have been linked mechanistically to the pathogenesis of cancer, as well as several other diseases. Second, small-molecule HDAC inhibitors (HDACi) exist that have the capacity to interfere with HDAC activity and can therefore achieve significant biological effects in preclinical models of cancer. These findings justified the introduction of HDACi into clinical trials. These initial clinical trials have just ended and show encouraging results. At this stage it is crucial to evaluate whether our current knowledge on the mechanisms of tumorigenesis that are linked to HDACs, and on the mechanisms of tumour sensitivity to HDACi, is firm enough to improve the design of further clinical trials. Recent structural and chemical data have emerged that will help in the design of novel HDACi with more desirable properties than the existing ones. However, key areas of investigation that might help to further illuminate the design of successful HDACi-based cancer therapy remain poorly explored. Novel findings indicate that our understanding of how HDACi work will probably change significantly, establishing a new paradigm in the field of intelligent drug design with broad implications for the design of targeted therapies in cancer and possibly other diseases.HDACs: enzymes looking for substrate(s) Four HDAC classes have been identified (FIG. 1a). One of them (class 3 or the so-called sirtuins, from the yeast protein Sir2) constitutes a structurally unrelated, NADdependent subfamily, and will not be considered here; neither will the class 3-specific HDACi, which are less characterized than those for the other classes 1 .An extensive phylogenetic analysis of HDACs has been performed 2,3 . HDACs are members of an ancient enzyme family found in animals, plants, fungi and bacteria. It is thought that HDACs evolved in the absence of histone proteins. Indeed, eukaryotic HDACs can deacetylate non-histone as well as histone substrates, and some HDACs reside in the cytoplasm (where histones are synthesized and acetylated for proper assembly, without the intervention of HDACs) and in mitochondria (where histones are absent).Are HDACs, then, truly HDACs 4 ? We postulate that key HDAC substrates might not be histones, but instead belong to the growing list of acetylated non-histone proteins (FIG. 1b and Supplementary information S1 ...

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“…HDACs are the enzymatic components of multiprotein complexes such as the N-CoR, SMRT, and Sin3 complexes (Zhang et al, 1997(Zhang et al, , 1999Xue et al, 1998;Guenther et al, 2000;Li et al, 2000;Wen et al, 2000;You et al, 2001;Humphrey et al, 2001;Yoon et al, 2003). Deacetylation of histone tails influences the interactions between histones and key transcriptional regulatory proteins (Iizuka and Smith, 2003).…”

Section: Eto Interactionsmentioning

confidence: 99%

ETO interacting proteins

Hug

Lazar

2004

Oncogene

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The 8;21 translocation produces a fusion between the ETO gene and that encoding the myeloid transcription factor AML1. The AML1-ETO fusion substitutes the majority of the ETO protein for the coregulator recruitment domains of AML1. Biochemical analyses of ETO have led to the identification of numerous interacting proteins including many corepressors. Importantly, the proteins interacting with ETO are different from those of wild-type AML1, suggesting that altered coregulator recruitment underlies the oncogenic properties of AML1-ETO. The list of corepressors capable of binding ETO includes histone deacetylases (HDACs) and components of distinct HDAC core complexes. These investigations have provided mechanistic insight into corepressor recruitment by ETO and clues to the leukemogenic activity of AML1-ETO.

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Stable Histone Deacetylase Complexes Distinguished by the Presence of SANT Domain Proteins CoREST/kiaa0071 and Mta-L1

Cited by 287 publications

References 52 publications

Proteomics Analysis of Ring1B/Rnf2 Interactors Identifies a Novel Complex with the Fbxl10/Jhdm1B Histone Demethylase and the Bcl6 Interacting Corepressor

Proteomics Analysis of Ring1B/Rnf2 Interactors Identifies a Novel Complex with the Fbxl10/Jhdm1B Histone Demethylase and the Bcl6 Interacting Corepressor

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

ETO interacting proteins

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