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Mol Cell Biol. 2011 Dec;31(23):4676-91. doi: 10.1128/MCB.05832-11. Epub 2011 Sep 19.

Identification of DHX33 as a mediator of rRNA synthesis and cell growth.

Author information

  • 1BRIGHT Institute, Department of Internal Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Abstract

In this report, we employed a lentiviral RNA interference screen to discover nucleolar DEAD/DEAH-box helicases involved in RNA polymerase I (Pol I)-mediated transcriptional activity. Our screen identified DHX33 as an important modulator of 47S rRNA transcription. We show that DHX33 is a cell cycle-regulated nucleolar protein that associates with ribosomal DNA (rDNA) loci, where it interacts with the RNA Pol I transcription factor upstream binding factor (UBF). DHX33 knockdown decreased the association of Pol I with rDNA and caused a dramatic decrease in levels of rRNA synthesis. Wild-type DHX33 overexpression, but not a DNA binding-defective mutant, enhanced 47S rRNA synthesis by promoting the association of RNA polymerase I with rDNA loci. In addition, an NTPase-defective DHX33 mutant (K94R) acted as a dominant negative mutant, inhibiting endogenous rRNA synthesis. Moreover, DHX33 deficiency in primary human fibroblasts triggered a nucleolar p53 stress response, resulting in an attenuation of proliferation. Thus, we show the mechanistic importance of DHX33 in rRNA transcription and proliferation.

PMID:
21930779
PMCID:
PMC3232920
DOI:
10.1128/MCB.05832-11
[PubMed - indexed for MEDLINE]
Free PMC Article
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