The identities of signal transducer proteins that integrate histone hypoacetylation and transcriptional repression are largely unknown. Here we demonstrate that THAP7, an uncharacterized member of the recently identified THAP (Thanatos-associated protein) family of proteins, is ubiquitously expressed, associates with chromatin, and represses transcription. THAP7 binds preferentially to hypoacetylated (un-, mono-, and diacetylated) histone H4 tails in vitro via its C-terminal 77 amino acids. Deletion of this domain, or treatment of cells with the histone deacetylase inhibitor TSA, which leads to histone hyperacetylation, partially disrupts THAP7/chromatin association in living cells. THAP7 coimmunoprecipitates with histone deacetylase 3 (HDAC3) and the nuclear hormone receptor corepressor (NCoR) and represses transcription as a Gal4 fusion protein. Chromatin immunoprecipitation assays demonstrate that these corepressors are recruited to promoters in a THAP7 dependent manner and promote histone H3 hypoacetylation. The conserved THAP domain is a key determinant for full HDAC3 association in vitro, and both the THAP domain and the histone interaction domain are important for the repressive properties of THAP7. Full repression mediated by THAP7 is also dependent on NCoR expression. We hypothesize that THAP7 is a dual function repressor protein that actively targets deacetylation of histone H3 necessary to establish transcriptional repression and functions as a signal transducer of the repressive mark of hypoacetylated histone H4. This is the first demonstration of the transcriptional regulatory properties of a human THAP domain protein, and a critical identification of a potential transducer of the repressive signal of hypoacetylated histone H4 in higher eukaryotes.
"The THAP-containing proteins act as transcriptional regulators linked to cell proliferation, cell cycle progression , maintenance of pluripotency, angiogenesis, apoptosis and epigenetic gene silencing (Roussigne et al. 2003a; Macfarlan et al. 2005; Cayrol et al. 2007; Dejosez et al. 2008; Balakrishnan et al. 2009). Within the human THAP family, THAP1 and THAP11 are the most characterized proteins at the functional level. "
[Show abstract][Hide abstract] ABSTRACT: The THAP (THanatos-Associated Protein) domain is an evolutionary conserved C2CH zinc-coordinating domain shared with a large family of cellular factors (THAP proteins). Many members of the THAP family act as transcription factors that control cell proliferation, cell cycle progression, angiogenesis, apoptosis and epigenetic gene silencing. They recognize specific DNA sequences in the promoters of target genes and subsequently recruit effector proteins. Recent structural and functional studies have allowed getting better insight into the nuclear and cellular functions of some THAP members and the molecular mechanisms by which they recognize DNA. The present article reviews recent advances in the knowledge of the THAP domains structures and their interaction with DNA, with a particular focus on NMR. It provides the solution structure of the THAP domain of THAP11, a recently characterized human THAP protein with important functions in transcription and cell growth in colon cancer.
"This class includes the subunits of INHAT complex; TAF-1α, TAF-1β, and pp32 as well as ataxin 3; silencing mediator or retinoid receptor corepressor (SMART)/nuclear hormone receptor corepressor (NcoR); proline-glutamic acid- and leucine-rich protein 1 (PELP1) [103–107]. Thanatos-associated protein 7 (THAP7) is known to associate with TAF-1β and to repress transcription by inhibition histone acetylation [108, 109]. A novel INHAT repressor (NIR) binds directly to nucleosomes and core histones and prevents acetylation by histone acetyltransferases, thus acting as a bona fide INHAT . "
[Show abstract][Hide abstract] ABSTRACT: Transcription factor, Jun dimerization protein 2 (JDP2), binds directly to histones and DNAs and then inhibits the p300-mediated acetylation both of core histones and of reconstituted nucleosomes that contain JDP2 recognition DNA sequences. JDP2 plays a key role as a repressor of adipocyte differentiation by regulation of the expression of the gene
via inhibition of histone acetylation. Moreover, JDP2-deficient mouse embryonic fibroblasts (JDP2−/− MEFs)
are resistant to replicative senescence. JDP2 inhibits the recruitment of polycomb repressive complexes (PRC1 and PRC2) to the promoter
of the gene encoding p16Ink4a, resulting from the inhibition of methylation of lysine 27 of histone H3 (H3K27). Therefore, it seems that chromatin-remodeling factors, including the PRC complex controlled by JDP2, may be important players in the senescence program. The novel mechanisms that underline the action of JDP2 in inducing cellular senescence and suppressing adipocyte differentiation are reviewed.
BioMed Research International 01/2011; 2011(6):569034. DOI:10.1155/2011/569034 · 2.71 Impact Factor
"These data suggest that THAP1 may modulate transcription, most likely as a repressor, either directly or in complex with other factors such as Par-4 (Roussigne et al., 2003a) or HCF-1 (Mazars et al., 2010). Similar roles in transcription have been suggested for other human THAPs, particularly THAP7 (Macfarlan et al., 2005 and 2006) and THAP11 (Zhu et al., 2009; Dejosez et al., 2010), as well as THAP orthologues in zebrafish (Giangrande et al. 2004) and C. elegans (Boxem and van den Heuvel, 2002; Fay et al., 2002). Structural studies of human (Campagne et al., 2010) and Drosophila (Sabogal et "
[Show abstract][Hide abstract] ABSTRACT: The hereditary dystonias comprise a set of diseases defined by a common constellation of motor deficits. These disorders are most likely associated with different molecular etiologies, many of which have yet to be elucidated. Here we discuss recent advances in three forms of hereditary dystonia, DYT1, DYT6 and DYT16, which share a similar clinical picture: onset in childhood or adolescence, progressive spread of symptoms with generalized involvement of body regions and a steady state affliction without treatment. Unlike DYT1, the genes responsible for DYT6 and DYT16 have only recently been identified, with relatively little information about the function of the encoded proteins. Nevertheless, recent data suggest that these proteins may fit together within interacting pathways involved in dopaminergic signaling, transcriptional regulation, and cellular stress responses. This review focuses on these molecular pathways, highlighting potential common themes among these dystonias which may serve as areas for future research. This article is part of a Special Issue entitled "Advances in dystonia".
Neurobiology of Disease 12/2010; 42(2):136-47. DOI:10.1016/j.nbd.2010.11.015 · 5.08 Impact Factor
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