Rrn3 Phosphorylation Is a Regulatory Checkpoint for Ribosome Biogenesis

Cavanaugh, Alice H.; Hirschler-Laszkiewicz, Iwona; Hu, Qiyue; Dundr, Miroslav; Smink, Tom; Misteli, Tom; Rothblum, Lawrence I.

doi:10.1074/jbc.m201232200

Cited by 83 publications

(121 citation statements)

References 58 publications

(71 reference statements)

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“…In contrast, our recently published data (28) indicate that the phosphorylation state of mammalian Rrn3 regulates this process. Aprikian et al (31) reported that yeast RNA pol I could be recruited to the rDNA promoter in the absence of Rrn3.…”

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confidence: 48%

“…Current models suggest that Rrn3 acts as a bridge between RNA pol I and the committed rDNA promoter (25)(26)(27)(28)(29). A direct interaction between the 43-kDa subunit of pol I (rpa43) and Rrn3 in the Rrn3⅐pol I complex was confirmed (27,28) as well as the direct interaction of human Rrn3 with the TAF I 110 and TAF I 63 subunits of species-specific transcription factor SL1 (28,29). Despite this body of knowledge, there are still significant controversies concerning the role that Rrn3 plays in transcription.…”

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confidence: 99%

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Rrn3 Becomes Inactivated in the Process of Ribosomal DNA Transcription

Hirschler-Laszkiewicz

Cavanaugh

Mirza

et al. 2003

Journal of Biological Chemistry

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The human homologue of yeast Rrn3, a 72-kDa protein, is essential for ribosomal DNA (rDNA) transcription. Although the importance of Rrn3 function in rDNA transcription is well established, its mechanism of action has not been determined. It has been suggested that the phosphorylation of either yeast RNA polymerase I or mammalian Rrn3 regulates the formation of RNA polymerase I⅐Rrn3 complexes that can interact with the committed template. These and other reported differences would have implications with respect to the mechanism by which Rrn3 functions in transcription. For example, in the yeast rDNA transcription system, Rrn3 might function catalytically, but in the mammalian system it might function stoichiometrically. Thus, we examined the question as to whether Rrn3 functions catalytically or stoichiometrically. We report that mammalian Rrn3 becomes the limiting factor as transcription reactions proceed. Moreover, we demonstrate that Rrn3 is inactivated during the transcription reactions. For example, Rrn3 isolated from a reaction that had undergone transcription cannot activate transcription in a subsequent reaction. We also show that this inactivated Rrn3 not only dissociates from RNA polymerase I, but is not capable of forming a stable complex with RNA polymerase I. Our results indicate that Rrn3 functions stoichiometrically in rDNA transcription and that its ability to associate with RNA polymerase I is lost upon transcription.

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confidence: 99%

Rrn3 Becomes Inactivated in the Process of Ribosomal DNA Transcription

Hirschler-Laszkiewicz

Cavanaugh

Mirza

et al. 2003

Journal of Biological Chemistry

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“…Once the on/off decision has been made, eukaryotic cells then appear to regulate the frequency at which RNA polymerase I initiates on each active gene in order to fine-tune the amount of rRNA produced. Studies in yeast and mammals indicate that fine-tuning is accomplished primarily through signal transduction mechanisms that lead to the post-translational modification of essential RNA polymerase I transcription factors [57][58][59][60][61][62].…”

Section: Rrna Gene Dosage Control Mechanisms and The Mammalian Norc Cmentioning

confidence: 99%

rRNA gene silencing and nucleolar dominance: Insights into a chromosome-scale epigenetic on/off switch

Preuss

Pikaard

2007

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

135

105

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Ribosomal RNA (rRNA) gene transcription accounts for most of the RNA in prokaryotic and eukaryotic cells. In eukaryotes, there are hundreds (to thousands) of rRNA genes tandemly repeated head-to-tail within nucleolus organizer regions (NORs) that span millions of basepairs. These nucleolar rRNA genes are transcribed by RNA Polymerase I (Pol I) and their expression is regulated according to the physiological need for ribosomes. Regulation occurs at several levels, one of which is an epigenetic on/off switch that controls the number of active rRNA genes. Additional mechanisms then fine-tune transcription initiation and elongation rates to dictate the total amount of rRNA produced per gene. In this review, we focus on the DNA and histone modifications that comprise the epigenetic on/off switch. In both plants and animals, this system is important for controlling the dosage of active rRNA genes. The dosage control system is also responsible for the chromatinmediated silencing of one parental set of rRNA genes in genetic hybrids, a large-scale epigenetic phenomenon known as nucleolar dominance.Keywords epigenetic phenomena; RNA polymerase I; DNA methylation; cytosine methylation; histone methylation; histone deacetylation; histone deacetylase; transcription; ribosomal RNA; nucleolus; nucleolus organizer region Large scale cytological effects of rRNA gene regulation: nucleolus and secondary constriction formationThe most prominent feature of a eukaryotic nucleus during interphase is the nucleolus (Figure 1), a region that contains relatively little chromosomal DNA but is rich in RNAs, proteins and ribonucleoprotein particles, including the large and small ribosome subunits as they undergo assembly [1][2][3]. The location of a nucleolus is not determined randomly; instead its formation is determined by the position of a discrete chromosomal locus known as a nucleolus organizer region, or NOR [4]. This fact was discovered based on an intriguing property: upon condensation of chromosomes at metaphase, NORs fail to condense to the same extent as surrounding chromosomal sequences and thus give rise to "secondary constrictions", with "primary constrictions" being defined as the centromeres (see Figure 1). Heitz initially noted that nucleoli form at, or very near, the sites of secondary constrictions [5] and McClintock soon thereafter obtained direct evidence [6]. She identified a maize line in which a chromosome break at or near the secondary constriction on chromosome 9, followed by translocation of one *Author to whom correspondence should be addressed: pikaard@biology2.wustl.edu, phone: Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the conte...

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“…Previous studies have identified essential components of the Pol I transcription apparatus as well as important cis-elements in Pol I promoters and revealed some potential mechanisms for regulation of transcription initiation (for reviews, see refs. [1][2][3][4][5]. Unlike Pol II, however, little is known regarding mechanisms that regulate postinitiation steps of transcription by Pol I.…”

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confidence: 99%

RNA polymerase II elongation factors Spt4p and Spt5p play roles in transcription elongation by RNA polymerase I and rRNA processing

Schneider

French

Osheim

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

103

143

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Previous investigations into the mechanisms that control RNA Polymerase (Pol) I transcription have primarily focused on the process of transcription initiation, thus little is known regarding postinitiation steps in the transcription cycle. Spt4p and Spt5p are conserved throughout eukaryotes, and they affect elongation by Pol II. We have found that these two proteins copurify with Pol I and associate with the rDNA in vivo. Disruption of the gene for Spt4p resulted in a modest decrease in growth and rRNA synthesis rates at the permissive temperature, 30°C. Furthermore, biochemical and EM analyses showed clear defects in rRNA processing. These data suggest that Spt4p, Spt5p, and, potentially, other regulators of Pol I transcription elongation play important roles in coupling rRNA transcription to its processing and ribosome assembly.yeast Saccharomyces cerevisiae T he synthesis of ribosomal RNA (rRNA) by RNA Polymerase (Pol) I is an important step in the synthesis of ribosomes, and its regulation is closely linked to the nutrient conditions and growth potential for the cell. Previous studies have identified essential components of the Pol I transcription apparatus as well as important cis-elements in Pol I promoters and revealed some potential mechanisms for regulation of transcription initiation (for reviews, see refs. 1-5). Unlike Pol II, however, little is known regarding mechanisms that regulate postinitiation steps of transcription by Pol I.One well characterized Pol II transcription elongation factor in yeast is a complex of two proteins, Spt4p and Spt5p (the complex will be referred to as Spt4͞5 here). The SPT4 and SPT5 genes were among many genes isolated for their ability to suppress transcription defects caused by insertions of the retrotransposon Ty1 (or the Ty1 long terminal repeats, ␦) in the 5Ј noncoding regions of yeast genes (6). Swanson and Winston (7) later showed that Spt4͞5 associates with Spt6p, which affects Pol II elongation through chromatin. However, Spt4p and Spt5p also form a separate complex, devoid of Spt6p, that associates with Pol II physically and genetically, and this interaction is important for transcription elongation (8). More recent work has shown that deletion of the nonessential gene SPT4 results in reduced efficiency of Pol II elongation through GC-rich DNA sequences (9) and a general decrease in Pol II processivity (10). Taken together, all of these data clearly support a role for Spt4͞5 in transcription elongation by Pol II in yeast.Spt4͞5 also plays a role in Pol II transcription elongation in mammalian cells. The mammalian homologues of Spt4p and Spt5p form a complex called the 5,6-dichloro-1-␤-Dribofuranosylbenzimidazole (DRB) sensitivity-inducing factor (DSIF), which was originally identified as a factor that induces a DRB-dependent arrest of elongating Pol II complexes in reconstituted in vitro transcription assays (11). It was demonstrated that under nucleotide-limiting conditions, DSIF could also increase the rate of elongation of Pol II in vitro. Thus, work in mam...

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Rrn3 Phosphorylation Is a Regulatory Checkpoint for Ribosome Biogenesis

Cited by 83 publications

References 58 publications

Rrn3 Becomes Inactivated in the Process of Ribosomal DNA Transcription

Rrn3 Becomes Inactivated in the Process of Ribosomal DNA Transcription

rRNA gene silencing and nucleolar dominance: Insights into a chromosome-scale epigenetic on/off switch

RNA polymerase II elongation factors Spt4p and Spt5p play roles in transcription elongation by RNA polymerase I and rRNA processing

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