NIR is a novel INHAT repressor that modulates the transcriptional activity of p53.
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.
Hublitz
Philip
P
Frauenklinik der Albert-Ludwigs-Universität Freiburg, Zentrale Klinische Forschung, D-79106 Freiburg, Germany.
Kunowska
Natalia
N
Mayer
Ulrich P
UP
Müller
Judith M
JM
Heyne
Kristina
K
Yin
Na
N
Fritzsche
Claudia
C
Poli
Cecilia
C
Miguet
Laurent
L
Schupp
Ingo W
IW
van Grunsven
Leo A
LA
Potiers
Noëlle
N
van Dorsselaer
Alain
A
Metzger
Eric
E
Roemer
Klaus
K
Schüle
Roland
R
D000818:Animals; D017209:Apoptosis; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
C507221:NIR protein, mouse; C507220:NOC2L protein, human; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051548:Histone Acetyltransferases