Regulation of Histone Acetylation and Transcription by INHAT, a Human Cellular Complex Containing the Set Oncoprotein

Abstract

Acetylation of histones by p300/CBP and PCAF is considered to be a critical step in transcriptional regulation. In order to understand the role of cellular activities that modulate histone acetylation and transcription, we have purified and characterized a multiprotein cellular complex that potently inhibits the histone acetyltransferase activity of p300/CBP and PCAF. We have mapped a novel acetyltransferase-inhibitory domain of this INHAT (inhibitor of acetyltransferases) complex that binds to histones and masks them from being acetyltransferase substrates. Endogenous INHAT subunits, which include the Set/TAF-Ibeta oncoprotein, associate with chromatin in vivo and can block coactivatormediated transcription when transfected in cells. We propose that histone masking by INHAT plays a regulatory role in chromatin modification and serves as a novel mechanism of transcriptional regulation.

Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity

“…Similar results were obtained by affinity chromatography using purified SET and GAPDH-Sepharose 4B columns (Figure 3b). Histones did not bind to GAPDH (data not shown), indicating that the association of histones with the GAPDH column might be indirect probably due to their ability to interact with SET (Seo et al, 2001). We subsequently aimed to characterize the interaction among p21 Cip1 , SET and GAPDH.…”

“…In addition to cell cycle regulation, SET also participates in a diversity of other functions as regulation of PP2A activity, chromatin remodeling and transcription, histone acetylation and apoptosis (Li et al, 1996;Okuwaki and Nagata, 1998;Seo et al, 2001;Cervoni et al, 2002;Fan et al, 2003). Thus, the association of GAPDH with SET could also be a new mechanism involved in the regulation of these cellular functions that merits to be explored in the next future.…”

“…It has been identified as a potent inhibitor of protein phosphatase 2A (Li et al, 1996;Adler et al, 1997;Pandey et al, 2003) and as a regulator of DNA replication, chromatin remodeling and gene transcription (Matsumoto et al, 1993;Okuwaki and Nagata, 1998;Shikama et al, 2000;Seo et al, 2001;Cervoni et al, 2002;Kutney et al, 2004).…”

“…The protein SET has been found associated with pp32, a protein considered to be a tumor suppressor, in two types of protein complexes, the INHAT complex (inhibitor of histone acetyltransferases) and the SET complex (Beresford et al, 2001;Seo et al, 2001;Fan et al, 2002;Kutney et al, 2004). Whereas the INHAT complex participates in chromatin remodelation by blocking the acetylation sites of histones, the SET complex has been proposed to be involved in the repair response to oxidative stress .…”

Histone chaperones in nucleosome eviction and histone exchange

“…There is evidence that NAP proteins are functional components of the p300 coactivator complex [60] and augment p300 enzymatic activity. The NAP1 homologue TAF1/ SET is a subunit of the INHAT complex, a multiprotein complex that inhibits the HAT activity of p300 and PCAF [61]. Another recently discovered NAP1 family member, Vps75, as well as Asf1, interact with the novel fungal histone acetyl transferase Rtt109 and appear to be required for HAT activity [62] [63].…”