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Role of c-Myc in the regulation of rDNA transcription by RNA polymerase I
Södertörn University, School of Life Sciences. Karolinska Intstitute.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)Text
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: urn:nbn:se:sh:diva-30693ISBN: 978-91-7409-948-5OAI: oai:DiVA.org:sh-30693DiVA: diva2:951000
Supervisors
Available from: 2016-08-04 Created: 2016-08-04 Last updated: 2016-08-04Bibliographically approved
List of papers
1. c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription
Open this publication in new window or tab >>c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription
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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.

National Category
Cell Biology
Identifiers
urn:nbn:se:sh:diva-14389 (URN)10.1038/ncb1225 (DOI)000227329800019 ()15723053 (PubMedID)2-s2.0-20044375377 (ScopusID)
Available from: 2011-12-22 Created: 2011-12-21 Last updated: 2016-08-04Bibliographically approved
2. c-Myc induces changes in higher order rDNA structure on stimulation of quiescent cells
Open this publication in new window or tab >>c-Myc induces changes in higher order rDNA structure on stimulation of quiescent cells
2009 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 28, no 16, 1833-1842 p.Article in journal (Refereed) Published
Abstract [en]

c-Myc is an oncogenic transcription factor capable of activating transcription by all three nuclear RNA polymerases, thus acting as a high-level coordinator of protein synthesis capacity and cell growth rate. c-Myc recruits RNA polymerase I-related transcription factors to the rDNA when quiescent cells are stimulated to re-enter the cell cycle. Using a model system of cell lines with variable c-Myc status, we show that on stimulation c-Myc rapidly induces gene loop structures in rDNA chromatin that juxtapose upstream and downstream rDNA sequences. c-Myc activation is both necessary and sufficient for this change in rDNA chromatin conformation. c-Myc activation induces association of TTF-1 with the rDNA, and c-Myc is physically associated with induced rDNA gene loops. The origins of two or more rDNA gene loops are closely juxtaposed, suggesting the possibility that c-Myc induces nucleolar chromatin hubs. Induction of rDNA gene loops may be an early step in the reprogramming of quiescent cells as they re-enter the growth cycle.

Keyword
c-Myc, nucleolus, transcription, ribosome biogenesis, RNA polymerase I
National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:sh:diva-17673 (URN)10.1038/onc.2009.21 (DOI)000265640500002 ()19270725 (PubMedID)2-s2.0-67349121053 (ScopusID)
Available from: 2012-12-14 Created: 2012-12-14 Last updated: 2016-08-04Bibliographically approved
3. c-Myc induces recruitment of rDNA genes to the nuclear matrix in response to cell growth stimulation
Open this publication in new window or tab >>c-Myc induces recruitment of rDNA genes to the nuclear matrix in response to cell growth stimulation
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-30692 (URN)
Note

Som manuskript i avhandling. As manuscript in dissertation.

Available from: 2016-08-04 Created: 2016-08-04 Last updated: 2016-08-04Bibliographically approved
4. Nucleolar organization, growth control and cancer
Open this publication in new window or tab >>Nucleolar organization, growth control and cancer
2010 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 5, no 3, 200-205 p.Article in journal (Refereed) Published
Abstract [en]

The nucleolus is a dynamic region of the nucleus that is disassembled and reformed each cell cycle and whose size is correlated with cell growth rate. Nucleolar size is a prognostic measure of cancer disease severity and increasing evidence suggests a causative role of nucleolar lesions in many cancers. In recent work (Shiue et al. Oncogene 28, 1833-42, 2009) we showed that the c-Myc oncoprotein induces changes in the higher order structure of rDNA chromatin in the nucleolus of growth stimulated quiescent rat cells. Here we show that c-Myc induces similar changes in human cells, that c-Myc plays a role in the overall structural integrity of the nucleolus and that c-Myc and its antagonistic partner Mad1 interact to program 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.

National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-30691 (URN)10.4161/epi.5.3.11376 (DOI)000276196400006 ()20305389 (PubMedID)2-s2.0-77954672013 (ScopusID)
Funder
The Foundation for Baltic and East European StudiesSwedish Research CouncilSwedish Cancer Society
Available from: 2016-08-04 Created: 2016-08-04 Last updated: 2016-08-04Bibliographically approved

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