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c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription
Södertörn University, School of Life Sciences. Karolinska Institutet.
SLU.
SLU.
German Cancer Research Center, Heidelberg, Germany.
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2005 (English)In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 7, no 3, 303-310 p.Article in journal (Refereed) Published
Abstract [en]

The c-Myc oncoprotein regulates transcription of genes that are associated with cell growth, proliferation and apoptosis(1). c-Myc levels are modulated by ubiquitin/proteasome-mediated degradation(1). Proteasome inhibition leads to c-Myc accumulation within nucleoli(2), indicating that c-Myc might have a nucleolar function. Here we show that the proteins c-Myc and Max interact in nucleoli and are associated with ribosomal DNA. This association is increased upon activation of quiescent cells and is followed by recruitment of the Myc cofactor TRRAP, enhanced histone acetylation, recruitment of RNA polymerase I (Pol I), and activation of rDNA transcription. Using small interfering RNAs (siRNAs) against c-Myc and an inhibitor of Myc - Max interactions, we demonstrate that c-Myc is required for activating rDNA transcription in response to mitogenic signals. Furthermore, using the ligand-activated MycER ( ER, oestrogen receptor) system, we show that c-Myc can activate Pol I transcription in the absence of Pol II transcription. These results suggest that c-Myc coordinates the activity of all three nuclear RNA polymerases, and thereby plays a key role in regulating ribosome biogenesis and cell growth.

Place, publisher, year, edition, pages
2005. Vol. 7, no 3, 303-310 p.
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:sh:diva-14389DOI: 10.1038/ncb1225ISI: 000227329800019PubMedID: 15723053ScopusID: 2-s2.0-20044375377OAI: oai:DiVA.org:sh-14389DiVA: diva2:469143
Available from: 2011-12-22 Created: 2011-12-21 Last updated: 2016-08-04Bibliographically approved
In thesis
1. Role of c-Myc in the regulation of rDNA transcription by RNA polymerase I
Open this publication in new window or tab >>Role of c-Myc in the regulation of rDNA transcription by RNA polymerase I
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ribosomal biogenesis and protein translation are finely coordinated with cell proliferation. All three RNA polymerases Pol I, II, and III are utilized for highly efficient and accurate ribosome production. The transcriptional activity of Pol I has been found to be a key determinant for ribosome biogenesis. As an immediate early gene, Myc can orchestrate the transcriptional activities of all RNA polymerases upon mitogenic stimulation. The direct roles of Myc-mediated Pol II & III transcription have been well studied, but that of Myc-mediated Pol I transcription remains unclear. Here we show that Myc with its obligatory partner Max colocalizes in nucleoli and Myc binds to ribosomal DNA, and that association of Myc to rDNA is followed by recruitment of the cofactor TRRAP which enhances histone acetylation. Using the ligand-activated MycE system, we also showed that c-Myc could activate Pol I transcription in the absence of Pol II transcription. Furthermore, using a model system of cell lines with variable Myc status, we showed that Myc rapidly induced gene loop structures in rDNA chromatin which juxtaposes upstream and downstream rDNA sequences. In addition, the origins of two or more rDNA gene loops are closely juxtaposed, suggesting the possibility that Myc induces nucleolar chromatin hubs. Next, we investigated the role of Myc in chromatin domain organization of rRNA genes and the compartmentalized distribution of nucleoli, and found that Myc mediated a spatial organization of mammalian rRNA genes into distinct chromatin loops by tethering to nucleolar matrix via their 5 and 3 nontranscribed spacer sequences. We found evidence that Myc corporated with co-activators to become a regulatory complex that governed the transcription of rRNA by orchestrating dynamic chromatin-loop architecture. Finally, we demonstrated that Myc plays a role in the overall structural integrity of the nucleolus and that Myc antagonized its antagonistic partner Mad1 programming the epigenetic status of rDNA chromatin. These changes are discussed in relation to current knowledge about nucleolar structure as well as the organization of chromosomes and transcription factories in nuclear regions outside the nucleolus.

Place, publisher, year, edition, pages
Stockholm: Karolinska Institutet, 2010. 59 p.
National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-30693 (URN)978-91-7409-948-5 (ISBN)
Supervisors
Available from: 2016-08-04 Created: 2016-08-04 Last updated: 2016-08-04Bibliographically approved

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