NIR is a novel INHAT repressor that modulates the transcriptional activity of p53

Abstract

Most transcriptional repression pathways depend on the targeted deacetylation of histone tails. In this report, we characterize NIR, a novel transcriptional corepressor with inhibitor of histone acetyltransferase (INHAT) activity. NIR (Novel INHAT Repressor) is ubiquitously expressed throughout embryonic development and adulthood. NIR is a potent transcriptional corepressor that is not blocked by histone deacetylase inhibitors and is capable of silencing both basal and activator-driven transcription. NIR directly binds to nucleosomes and core histones and prevents acetylation by histone acetyltransferases, thus acting as a bona fide INHAT. Using a tandem affinity purification approach, we identified the tumor suppressor p53 as a NIR-interacting partner. Association of p53 and NIR was verified in vitro and in vivo. Upon recruitment by p53, NIR represses transcription of both p53-dependent reporters and endogenous target genes. Knock-down of NIR by RNA interference significantly enhances histone acetylation at p53-regulated promoters. Moreover, p53-dependent apoptosis is robustly increased upon depletion of NIR. In summary, our findings describe NIR as a novel INHAT that plays an important role in the control of p53 function.[Keywords: INHAT; transcription; HDAC-independent repression; p53] Supplemental material is available at http://www.genesdev.org.

REBELOTE,SQUINT, andULTRAPETALA1Function Redundantly in the Temporal Regulation of Floral Meristem Termination inArabidopsis thaliana

“…NOC2 was shown to be essential for embryonic development in Caenorhabditis elegans (Kamath et al, 2003) and zebra fish (Amsterdam et al, 2004). Interestingly, a human NOC2-containing protein has been identified as an inhibitor of histone acetyltransferase activity (Hublitz et al, 2005).…”

Aurora B Interacts with NIR-p53, Leading to p53 Phosphorylation in Its DNA-binding Domain and Subsequent Functional Suppression

“…Interestingly, one gene called DKFZp564C186 was also identified in this analysis. This gene attracted our attention as later on it was functionally characterized and renamed as NIR (novel INHAT repressor) (14). To validate the microarray result, we treated CD19ϩ B cells with CD40L plus IL4 and harvested cell lysates at different time points for immunoblot analysis of NIR expression.…”

“…As a nuclear protein, NIR has been shown to directly bind to nucleosomes and core histones and prevent acetylation by histone acetyltransferases. Moreover, NIR also physically interacts with p53 and localizes to the promoter regions of some p53-targeted genes, thus suppressing p53 transcriptional activity and p53-dependent apoptosis (14). We previously found that the expression level of NIR (DKFZp564C186) increased in normal B cells upon stimulation with CD40L plus IL-4 (15).…”

“…NIR (novel INHAT repressor) has been identified as a potent transcriptional co-repressor with inhibitor of histone acetyltransferase (INHAT) activity (14). As a nuclear protein, NIR has been shown to directly bind to nucleosomes and core histones and prevent acetylation by histone acetyltransferases.…”

Repression of New p53 Targets Revealed by ChIP on Chip Experiments

“…However, interactions with repressor complexes emerged. 8,23,28 Specifically, there are two categories of genes being repressed: anti-apoptotic [10][11][12][13] and genes active in the G 2 /M phase of the cell cycle. [20][21][22][23] The latter promoters are strongly downmodulated by treatment of cells with DNA-damaging agents, or by p53 overexpression, without any recognizable binding element (reviewed in ref.…”