Regulation of RNA Polymerase I Transcription in Development, Disease, and Aging

2018 ◽  
Vol 87 (1) ◽  
pp. 51-73 ◽  
Author(s):  
Samim Sharifi ◽  
Holger Bierhoff
Keyword(s):  
Ribosome Biogenesis ◽  
Rna Polymerase I ◽  
Rrna Genes ◽  
Rrna Gene ◽  
Environmental Signals ◽  
Pol I ◽  
Nuclear Rna ◽  
Multicopy Genes ◽  
Polymerase I ◽  
Precursor Transcript

Ribosome biogenesis is a complex and highly energy-demanding process that requires the concerted action of all three nuclear RNA polymerases (Pol I–III) in eukaryotes. The three largest ribosomal RNAs (rRNAs) originate from a precursor transcript (pre-rRNA) that is encoded by multicopy genes located in the nucleolus. Transcription of these rRNA genes (rDNA) by Pol I is the key regulation step in ribosome production and is tightly controlled by an intricate network of signaling pathways and epigenetic mechanisms. In this article, we give an overview of the composition of the basal Pol I machinery and rDNA chromatin. We discuss rRNA gene regulation in response to environmental signals and developmental cues and focus on perturbations occurring in diseases linked to either excessive or limited rRNA levels. Finally, we discuss the emerging view that rDNA integrity and activity may be involved in the aging process.

scholarly journals Structure and function of ribosomal RNA gene chromatin

2008 ◽  
Vol 36 (4) ◽  
pp. 619-624 ◽  
Author(s):  
Joanna L. Birch ◽  
Joost C.B.M. Zomerdijk
Keyword(s):  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Rna Polymerase I ◽  
Rrna Genes ◽  
Rrna Gene ◽  
Pol I ◽  
And Function ◽  
Polymerase I ◽  
Cell Growth And Proliferation ◽  
Cellular Control

Transcription of the major ribosomal RNAs by Pol I (RNA polymerase I) is a key determinant of ribosome biogenesis, driving cell growth and proliferation in eukaryotes. Hundreds of copies of rRNA genes are present in each cell, and there is evidence that the cellular control of Pol I transcription involves adjustments to the number of rRNA genes actively engaged in transcription, as well as to the rate of transcription from each active gene. Chromatin structure is inextricably linked to rRNA gene activity, and the present review highlights recent advances in this area.

scholarly journals Regulation of Ribosomal RNA Production by RNA Polymerase I: Does Elongation Come First?

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Benjamin Albert ◽  
Jorge Perez-Fernandez ◽  
Isabelle Léger-Silvestre ◽  
Olivier Gadal
Keyword(s):  
Rna Polymerase ◽  
Ribosomal Rna ◽  
Chromatin Structure ◽  
Rna Polymerase I ◽  
Rrna Genes ◽  
Rrna Gene ◽  
Elongation Factors ◽  
Pol I ◽  
Polymerase I

Ribosomal RNA (rRNA) production represents the most active transcription in the cell. Synthesis of the large rRNA precursors (35–47S) can be achieved by up to 150 RNA polymerase I (Pol I) enzymes simultaneously transcribing each rRNA gene. In this paper, we present recent advances made in understanding the regulatory mechanisms that control elongation. Built-in Pol I elongation factors, such as Rpa34/Rpa49 in budding yeast and PAF53/CAST in humans, are instrumental to the extremely high rate of rRNA production per gene. rRNA elongation mechanisms are intrinsically linked to chromatin structure and to the higher-order organization of the rRNA genes (rDNA). Factors such as Hmo1 in yeast and UBF1 in humans are key players in rDNA chromatin structure in vivo. Finally, elongation factors known to regulate messengers RNA production by RNA polymerase II are also involved in rRNA production and work cooperatively with Rpa49 in vivo.

scholarly journals Epigenetic Programming of the rRNA Promoter by MBD3

2007 ◽  
Vol 27 (13) ◽  
pp. 4938-4952 ◽  
Author(s):  
Shelley E. Brown ◽  
Moshe Szyf
Keyword(s):  
Small Interfering Rna ◽  
Rna Polymerase I ◽  
Rrna Genes ◽  
Rrna Gene ◽  
Rrna Transcription ◽  
Epigenetic Programming ◽  
Binding Factor ◽  
Upstream Binding Factor ◽  
Polymerase I ◽  
Interfering Rna

ABSTRACT Within the human genome there are hundreds of copies of the rRNA gene, but only a fraction of these genes are active. Silencing through epigenetics has been extensively studied; however, it is essential to understand how active rRNA genes are maintained. Here, we propose a role for the methyl-CpG binding domain protein MBD3 in epigenetically maintaining active rRNA promoters. We show that MBD3 is localized to the nucleolus, colocalizes with upstream binding factor, and binds to unmethylated rRNA promoters. Knockdown of MBD3 by small interfering RNA results in increased methylation of the rRNA promoter coupled with a decrease in RNA polymerase I binding and pre-rRNA transcription. Conversely, overexpression of MBD3 results in decreased methylation of the rRNA promoter. Additionally, overexpression of MBD3 induces demethylation of nonreplicating plasmids containing the rRNA promoter. We demonstrate that this demethylation occurs following the overexpression of MBD3 and its increased interaction with the methylated rRNA promoter. This is the first demonstration that MBD3 is involved in inducing and maintaining the demethylated state of a specific promoter.

scholarly journals Dichotomous Impact of Myc on rRNA Gene Activation and Silencing in B Cell Lymphomagenesis

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3009
Author(s):  
Gaurav Joshi ◽  
Alexander Otto Eberhardt ◽  
Lisa Lange ◽  
René Winkler ◽  
Steve Hoffmann ◽  
...  
Keyword(s):  
B Cell ◽  
Gene Activation ◽  
Cpg Methylation ◽  
Rrna Genes ◽  
Rrna Gene ◽  
Rdna Transcription ◽  
Highly Active ◽  
Pol I ◽  
Polymerase I ◽  
Transcriptional Output

A major transcriptional output of cells is ribosomal RNA (rRNA), synthesized by RNA polymerase I (Pol I) from multicopy rRNA genes (rDNA). Constitutive silencing of an rDNA fraction by promoter CpG methylation contributes to the stabilization of these otherwise highly active loci. In cancers driven by the oncoprotein Myc, excessive Myc directly stimulates rDNA transcription. However, it is not clear when during carcinogenesis this mechanism emerges, and how Myc-driven rDNA activation affects epigenetic silencing. Here, we have used the Eµ-Myc mouse model to investigate rDNA transcription and epigenetic regulation in Myc-driven B cell lymphomagenesis. We have developed a refined cytometric strategy to isolate B cells from the tumor initiation, promotion, and progression phases, and found a substantial increase of both Myc and rRNA gene expression only in established lymphoma. Surprisingly, promoter CpG methylation and the machinery for rDNA silencing were also strongly up-regulated in the tumor progression state. The data indicate a dichotomous role of oncogenic Myc in rDNA regulation, boosting transcription as well as reinforcing repression of silent repeats, which may provide a novel angle on perturbing Myc function in cancer cells.

scholarly journals Drug-induced dispersal of transcribed rRNA genes and transcriptional products: immunolocalization and silver staining of different nucleolar components in rat cells treated with 5,6-dichloro-beta-D-ribofuranosylbenzimidazole.

1984 ◽  
Vol 99 (2) ◽  
pp. 672-679 ◽  
Author(s):  
U Scheer ◽  
B Hügle ◽  
R Hazan ◽  
K M Rose
Keyword(s):  
Rna Polymerase ◽  
Organizer Region ◽  
Nucleolar Organizer Region ◽  
Ribosomal Subunit ◽  
Rna Polymerase I ◽  
Rrna Genes ◽  
Rrna Gene ◽  
Linear Distribution ◽  
Nucleolar Material ◽  
Polymerase I

Upon incubation of cultured rat cells with the adenosine analogue 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), nucleoli reversibly dissociate into their substructures, disperse throughout the nuclear interior, and form nucleolar "necklaces". We have used this experimental system, which does not inhibit transcription of the rRNA genes, to study by immunocytochemistry the distribution of active rRNA genes and their transcriptional products during nucleolar dispersal and recovery to normal morphology. Antibodies to RNA polymerase I allow detection of template-engaged polymerase, and monoclonal antibodies to a ribosomal protein (S1) of the small ribosomal subunit permit localization of nucleolar preribosomal particles. The results show that, under the action of DRB transcribed rRNA, genes spread throughout the nucleoplasm and finally appear in the form of several rows, each containing several (up to 30) granules positive for RNA polymerase I and argyrophilic proteins. Nucleolar material containing preribosomal particles also appears in granular structures spread over the nucleoplasm but its distribution is distinct from that of rRNA gene-containing granules. We conclude that, although transcriptional units and preribosomal particles are both redistributed in response to DRB, these entities retain their individuality as functionally defined subunits. We further propose that each RNA polymerase-positive granular unit represents a single transcription unit and that each continuous array of granules ("string of nucleolar beads") reflects the linear distribution of rRNA genes along a nucleolar organizer region. Based on the total number of polymerase I-positive granules we estimate that a minimum of 60 rRNA genes are active during interphase of DRB-treated rat cells.

scholarly journals Che-1/AATF binds to RNA polymerase I machinery and sustains ribosomal RNA gene transcription

2020 ◽  
Vol 48 (11) ◽  
pp. 5891-5906 ◽  
Author(s):  
Cristina Sorino ◽  
Valeria Catena ◽  
Tiziana Bruno ◽  
Francesca De Nicola ◽  
Stefano Scalera ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Rna Polymerase ◽  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Cellular Proliferation ◽  
Rna Polymerase I ◽  
Rrna Synthesis ◽  
Rrna Gene ◽  
Response To Stress ◽  
Polymerase I

Abstract Originally identified as an RNA polymerase II interactor, Che-1/AATF (Che-1) has now been recognized as a multifunctional protein involved in cell-cycle regulation and cancer progression, as well as apoptosis inhibition and response to stress. This protein displays a peculiar nucleolar localization and it has recently been implicated in pre-rRNA processing and ribosome biogenesis. Here, we report the identification of a novel function of Che-1 in the regulation of ribosomal RNA (rRNA) synthesis, in both cancer and normal cells. We demonstrate that Che-1 interacts with RNA polymerase I and nucleolar upstream binding factor (UBF) and promotes RNA polymerase I-dependent transcription. Furthermore, this protein binds to the rRNA gene (rDNA) promoter and modulates its epigenetic state by contrasting the recruitment of HDAC1. Che-1 downregulation affects RNA polymerase I and UBF recruitment on rDNA and leads to reducing rDNA promoter activity and 47S pre-rRNA production. Interestingly, Che-1 depletion induces abnormal nucleolar morphology associated with re-distribution of nucleolar proteins. Finally, we show that upon DNA damage Che-1 re-localizes from rDNA to TP53 gene promoter to induce cell-cycle arrest. This previously uncharacterized function of Che-1 confirms the important role of this protein in the regulation of ribosome biogenesis, cellular proliferation and response to stress.

scholarly journals RNA polymerase I–specific subunits promote polymerase clustering to enhance the rRNA gene transcription cycle

2011 ◽  
Vol 192 (2) ◽  
pp. 277-293 ◽  
Author(s):  
Benjamin Albert ◽  
Isabelle Léger-Silvestre ◽  
Christophe Normand ◽  
Martin K. Ostermaier ◽  
Jorge Pérez-Fernández ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Loading Rate ◽  
Gene Copy Number ◽  
Ribosomal Gene ◽  
Rna Polymerase I ◽  
Gene Copy ◽  
Rrna Gene ◽  
Pol I ◽  
Pol Iii ◽  
Polymerase I

RNA polymerase I (Pol I) produces large ribosomal RNAs (rRNAs). In this study, we show that the Rpa49 and Rpa34 Pol I subunits, which do not have counterparts in Pol II and Pol III complexes, are functionally conserved using heterospecific complementation of the human and Schizosaccharomyces pombe orthologues in Saccharomyces cerevisiae. Deletion of RPA49 leads to the disappearance of nucleolar structure, but nucleolar assembly can be restored by decreasing ribosomal gene copy number from 190 to 25. Statistical analysis of Miller spreads in the absence of Rpa49 demonstrates a fourfold decrease in Pol I loading rate per gene and decreased contact between adjacent Pol I complexes. Therefore, the Rpa34 and Rpa49 Pol I–specific subunits are essential for nucleolar assembly and for the high polymerase loading rate associated with frequent contact between adjacent enzymes. Together our data suggest that localized rRNA production results in spatially constrained rRNA production, which is instrumental for nucleolar assembly.

scholarly journals RNA Polymerase I-Specific Subunit CAST/hPAF49 Has aRole in the Activation of Transcription by UpstreamBinding Factor

2006 ◽  
Vol 26 (14) ◽  
pp. 5436-5448 ◽  
Author(s):  
Kostya I. Panov ◽  
Tatiana B. Panova ◽  
Olivier Gadal ◽  
Kaori Nishiyama ◽  
Takashi Saito ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
T Cell Activation ◽  
Conformational Changes ◽  
Cell Activation ◽  
Rna Polymerase I ◽  
Rrna Genes ◽  
28S Rrna ◽  
Pol I ◽  
Activation Of Transcription ◽  
Polymerase I

ABSTRACT Eukaryotic RNA polymerases are large complexes, 12 subunits of which are structurally or functionally homologous across the three polymerase classes. Each class has a set of specific subunits, likely targets of their cognate transcription factors. We have identified and characterized a human RNA polymerase I (Pol I)-specific subunit, previously identified as ASE-1 (antisense of ERCC1) and as CD3ε-associated signal transducer (CAST), and here termed CAST or human Pol I-associated factor of 49 kDa (hPAF49), after mouse orthologue PAF49. We provide evidence for growth-regulated Tyr phosphorylation of CAST/hPAF49, specifically in initiation-competent Pol Iβ complexes in HeLa cells, at a conserved residue also known to be important for signaling during T-cell activation. CAST/hPAF49 can interact with activator upstream binding factor (UBF) and, weakly, with selectivity factor 1 (SL1) at the rDNA (ribosomal DNA repeat sequence encoding the 18S, 5.8S, and 28S rRNA genes) promoter. CAST/hPAF49-specific antibodies and excess CAST/hPAF49 protein, which have no effect on basal Pol I transcription, inhibit UBF-activated transcription following functional SL1-Pol I-rDNA complex assembly and disrupt the interaction of UBF with CAST/hPAF49, suggesting that interaction of this Pol I-specific subunit with UBF is crucial for activation. Drawing on parallels between mammalian and Saccharomyces cerevisiae Pol I transcription machineries, we advance one model for CAST/hPAF49 function in which the network of interactions of Pol I-specific subunits with UBF facilitates conformational changes of the polymerase, leading to stabilization of the Pol I-template complex and, thereby, activation of transcription.

scholarly journals The dynamic assembly of distinct RNA polymerase I complexes modulates rDNA transcription

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Eva Torreira ◽  
Jaime Alegrio Louro ◽  
Irene Pazos ◽  
Noelia González-Polo ◽  
David Gil-Carton ◽  
...  
Keyword(s):  
Cell Growth ◽  
Rna Polymerase ◽  
Ribosome Biogenesis ◽  
Mutational Analysis ◽  
Rna Polymerase I ◽  
Initiation Factor ◽  
Rdna Transcription ◽  
Pol I ◽  
Polymerase I

Cell growth requires synthesis of ribosomal RNA by RNA polymerase I (Pol I). Binding of initiation factor Rrn3 activates Pol I, fostering recruitment to ribosomal DNA promoters. This fundamental process must be precisely regulated to satisfy cell needs at any time. We present in vivo evidence that, when growth is arrested by nutrient deprivation, cells induce rapid clearance of Pol I–Rrn3 complexes, followed by the assembly of inactive Pol I homodimers. This dual repressive mechanism reverts upon nutrient addition, thus restoring cell growth. Moreover, Pol I dimers also form after inhibition of either ribosome biogenesis or protein synthesis. Our mutational analysis, based on the electron cryomicroscopy structures of monomeric Pol I alone and in complex with Rrn3, underscores the central role of subunits A43 and A14 in the regulation of differential Pol I complexes assembly and subsequent promoter association.

scholarly journals Metastasis-related methyltransferase 1 (Merm1) represses the methyltransferase activity of Dnmt3a and facilitates RNA polymerase I transcriptional elongation

2018 ◽  
Vol 11 (1) ◽  
pp. 78-90
Author(s):  
Guoliang Lyu ◽  
Le Zong ◽  
Chao Zhang ◽  
Xiaoke Huang ◽  
Wenbing Xie ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Dna Methyltransferase ◽  
Rna Polymerase I ◽  
Rrna Genes ◽  
Binding Motif ◽  
Rrna Gene ◽  
Transcriptional Elongation ◽  
Methyltransferase Activity ◽  
Polymerase I ◽  
Methyltransferase 1

Abstract Stimulatory regulators for DNA methyltransferase activity, such as Dnmt3L and some Dnmt3b isoforms, affect DNA methylation patterns, thereby maintaining gene body methylation and maternal methylation imprinting, as well as the methylation landscape of pluripotent cells. Here we show that metastasis-related methyltransferase 1 (Merm1), a protein deleted in individuals with Williams–Beuren syndrome, acts as a repressive regulator of Dnmt3a. Merm1 interacts with Dnmt3a and represses its methyltransferase activity with the requirement of the binding motif for S-adenosyl-L-methionine. Functional analysis of gene regulation revealed that Merm1 is capable of maintaining hypomethylated rRNA gene bodies and co-localizes with RNA polymerase I in the nucleolus. Dnmt3a recruits Merm1, and in return, Merm1 ensures the binding of Dnmt3a to hypomethylated gene bodies. Such interplay between Dnmt3a and Merm1 facilitates transcriptional elongation by RNA polymerase I. Our findings reveal a repressive factor for Dnmt3a and uncover a molecular mechanism underlying transcriptional elongation of rRNA genes.

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