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RESEARCH PAPER

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

¹ Frauenklinik der Albert-Ludwigs-Universität Freiburg, Zentrale Klinische Forschung, D-79106 Freiburg, Germany; ² University of Saarland Medical School, Institute of Virology, D-66421 Homburg, Germany; ³ Laboratoire de Spectrométrie de Masse Bio-Organique, Ecole de Chimie, Polymères et Matériaux, F-67089 Strasbourg, France; ⁴ Deutsches Krebsforschungszentrum DKFZ, Abteilung Molekulare Genomanalyse, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany; ⁵ Department of Developmental Biology, VIB and Laboratory of Molecular Biology (Celgen), University of Leuven, B-3000 Leuven, Belgium

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]

Received May 11, 2005; revised version accepted September 22, 2005.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.351205.

⁶ These authors contributed equally to this work.

⁷ Corresponding author.

E-MAIL roland.schuele{at}uniklinik-freiburg.de; FAX 49-761-270-6311.

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