scholarly journals Nucleolar and Ribosomal Dysfunction—A Common Pathomechanism in Childhood Progerias?

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 534 ◽  
Author(s):  
Tamara Phan ◽  
Fatima Khalid ◽  
Sebastian Iben
Keyword(s):  
Endoplasmic Reticulum ◽  
Ribosome Biogenesis ◽  
Subcutaneous Fat ◽  
Rna Polymerase I ◽  
Premature Aging ◽  
Ribosomal Biogenesis ◽  
Rdna Transcription ◽  
Rrna Transcription ◽  
Pol I ◽  
Polymerase I

The nucleolus organizes around the sites of transcription by RNA polymerase I (RNA Pol I). rDNA transcription by this enzyme is the key step of ribosome biogenesis and most of the assembly and maturation processes of the ribosome occur co-transcriptionally. Therefore, disturbances in rRNA transcription and processing translate to ribosomal malfunction. Nucleolar malfunction has recently been described in the classical progeria of childhood, Hutchinson–Gilford syndrome (HGPS), which is characterized by severe signs of premature aging, including atherosclerosis, alopecia, and osteoporosis. A deregulated ribosomal biogenesis with enlarged nucleoli is not only characteristic for HGPS patients, but it is also found in the fibroblasts of “normal” aging individuals. Cockayne syndrome (CS) is also characterized by signs of premature aging, including the loss of subcutaneous fat, alopecia, and cataracts. It has been shown that all genes in which a mutation causes CS, are involved in rDNA transcription by RNA Pol I. A disturbed ribosomal biogenesis affects mitochondria and translates into ribosomes with a reduced translational fidelity that causes endoplasmic reticulum (ER) stress and apoptosis. Therefore, it is speculated that disease-causing disturbances in the process of ribosomal biogenesis may be more common than hitherto anticipated.

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 The Splicing ATPase Prp43p Is a Component of Multiple Preribosomal Particles

2005 ◽  
Vol 25 (21) ◽  
pp. 9269-9282 ◽  
Author(s):  
Simon Lebaron ◽  
Carine Froment ◽  
Micheline Fromont-Racine ◽  
Jean-Christophe Rain ◽  
Bernard Monsarrat ◽  
...  
Keyword(s):  
Affinity Purification ◽  
Rna Polymerase I ◽  
Rrna Processing ◽  
Rrna Transcription ◽  
Pol I ◽  
Final Maturation ◽  
Steady State Levels ◽  
Splicing Defects ◽  
Polymerase I ◽  
Two Hybrid

ABSTRACT Prp43p is a putative helicase of the DEAH family which is required for the release of the lariat intron from the spliceosome. Prp43p could also play a role in ribosome synthesis, since it accumulates in the nucleolus. Consistent with this hypothesis, we find that depletion of Prp43p leads to accumulation of 35S pre-rRNA and strongly reduces levels of all downstream pre-rRNA processing intermediates. As a result, the steady-state levels of mature rRNAs are greatly diminished following Prp43p depletion. We present data arguing that such effects are unlikely to be solely due to splicing defects. Moreover, we demonstrate by a combination of a comprehensive two-hybrid screen, tandem-affinity purification followed by mass spectrometry, and Northern analyses that Prp43p is associated with 90S, pre-60S, and pre-40S ribosomal particles. Prp43p seems preferentially associated with Pfa1p, a novel specific component of pre-40S ribosomal particles. In addition, Prp43p interacts with components of the RNA polymerase I (Pol I) transcription machinery and with mature 18S and 25S rRNAs. Hence, Prp43p might be delivered to nascent 90S ribosomal particles during pre-rRNA transcription and remain associated with preribosomal particles until their final maturation steps in the cytoplasm. Our data also suggest that the ATPase activity of Prp43p is required for early steps of pre-rRNA processing and normal accumulation of mature rRNAs.

scholarly journals Role of TATA Binding Protein (TBP) in Yeast Ribosomal DNA Transcription by RNA Polymerase I: Defects in the Dual Functions of Transcription Factor UAF Cannot Be Suppressed by TBP

2001 ◽  
Vol 21 (7) ◽  
pp. 2292-2297 ◽  
Author(s):  
Imran Siddiqi ◽  
John Keener ◽  
Loan Vu ◽  
Masayasu Nomura
Keyword(s):  
Rna Polymerase ◽  
Ribosomal Dna ◽  
Binding Protein ◽  
Tata Binding Protein ◽  
Rna Polymerase I ◽  
Pol Ii ◽  
Rrna Transcription ◽  
Pol I ◽  
Mutant Strains ◽  
Polymerase I

ABSTRACT Initiation of ribosomal DNA (rDNA) transcription by RNA polymerase I (Pol I) in the yeast Saccharomyces cerevisiae involves upstream activation factor (UAF), core factor, the TATA binding protein (TBP), and Rrn3p in addition to Pol I. We found previously that yeast strains carrying deletions in the UAF component RRN9switch completely to the use of Pol II for rRNA transcription, with no residual Pol I transcription. These polymerase-switched strains initially grow very slowly, but subsequent expansion in the number of rDNA repeats on chromosome XII leads to better growth. Recently, it was reported that TBP overexpression could bypass the requirement of UAF for Pol I transcription in vivo, producing nearly wild-type levels of growth in UAF mutant strains (P. Aprikian, B. Moorefield, and R. H. Reeder, Mol. Cell. Biol. 20:5269–5275, 2000). Here, we demonstrate that deletions in the UAF component RRN5,RRN9, or RRN10 lead to Pol II transcription of rDNA. TBP overexpression does not suppress UAF mutation, and these strains continue to use Pol II for rRNA transcription. We do not find evidence for even low levels of Pol I transcription in UAF mutant strains carrying overexpressed TBP. In diploid strains lacking both copies of the UAF componentRRN9, Pol II transcription of rDNA is more strongly repressed than in haploid strains but TBP overexpression still fails to activate Pol I. These results emphasize that UAF plays an essential role in activation of Pol I transcription and silencing of Pol II transcription of rDNA and that TBP functions to recruit the Pol I machinery in a manner completely dependent on UAF.

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 Nucleolar TFIIE plays a role in ribosomal biogenesis and performance

2020 ◽  
Author(s):  
Tamara Phan ◽  
Pallab Maity ◽  
Christina Ludwig ◽  
Lisa Streit ◽  
Jens Michaelis ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Ribosome Biogenesis ◽  
Initiation Site ◽  
Rna Polymerase I ◽  
Ribosomal Biogenesis ◽  
Protein Coding ◽  
Degenerative Disorder ◽  
And Performance ◽  
Polymerase I

Ribosome biogenesis is a highly energy-demanding process in eukaryotes which requires the concerted action of all three RNA polymerases. In RNA polymerase II transcription, the general transcription factor TFIIH is recruited by TFIIE to the initiation site of protein-coding genes. Distinct mutations in TFIIH and TFIIE give rise to the degenerative disorder trichothiodystrophy (TTD). Here we uncovered an unexpected role of TFIIE in ribosomal RNA synthesis by RNA polymerase I. With high resolution microscopy we detected TFIIE in the nucleolus where TFIIE binds to actively transcribed rDNA. Mutations in TFIIE affects gene-occupancy of RNA polymerase I, rRNA maturation, ribosomal assembly and performance. In consequence, the elevated translational error rate with imbalanced protein synthesis and turnover results in an increase in heat-sensitive proteins. Collectively, mutations in TFIIE - due to impaired ribosomal biogenesis and translational accuracy - lead to a loss of protein homeostasis (proteostasis) which can partly explain the clinical phenotype in TTD.

scholarly journals Ribosomal RNA Transcription Regulation in Breast Cancer

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 502
Author(s):  
Cecelia M. Harold ◽  
Amber F. Buhagiar ◽  
Yan Cheng ◽  
Susan J. Baserga
Keyword(s):  
Breast Cancer ◽  
Rna Polymerase ◽  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Rna Polymerase I ◽  
Cancer Therapies ◽  
Rdna Transcription ◽  
Global Protein Synthesis ◽  
Novel Drugs ◽  
Polymerase I

Ribosome biogenesis is a complex process that is responsible for the formation of ribosomes and ultimately global protein synthesis. The first step in this process is the synthesis of the ribosomal RNA in the nucleolus, transcribed by RNA Polymerase I. Historically, abnormal nucleolar structure is indicative of poor cancer prognoses. In recent years, it has been shown that ribosome biogenesis, and rDNA transcription in particular, is dysregulated in cancer cells. Coupled with advancements in screening technology that allowed for the discovery of novel drugs targeting RNA Polymerase I, this transcriptional machinery is an increasingly viable target for cancer therapies. In this review, we discuss ribosome biogenesis in breast cancer and the different cellular pathways involved. Moreover, we discuss current therapeutics that have been found to affect rDNA transcription and more novel drugs that target rDNA transcription machinery as a promising avenue for breast cancer treatment.

scholarly journals Phosphorylation by Casein Kinase 2 Facilitates rRNA Gene Transcription by Promoting Dissociation of TIF-IA from Elongating RNA Polymerase I

2008 ◽  
Vol 28 (16) ◽  
pp. 4988-4998 ◽  
Author(s):  
Holger Bierhoff ◽  
Miroslav Dundr ◽  
Annemieke A. Michels ◽  
Ingrid Grummt
Keyword(s):  
Rna Polymerase ◽  
Transcription Initiation ◽  
Casein Kinase ◽  
Casein Kinase 2 ◽  
Rna Polymerase I ◽  
Initiation Factor ◽  
Rrna Gene ◽  
Rdna Transcription ◽  
Pol I ◽  
Polymerase I

ABSTRACT The protein kinase casein kinase 2 (CK2) phosphorylates different components of the RNA polymerase I (Pol I) transcription machinery and exerts a positive effect on rRNA gene (rDNA) transcription. Here we show that CK2 phosphorylates the transcription initiation factor TIF-IA at serines 170 and 172 (Ser170/172), and this phosphorylation triggers the release of TIF-IA from Pol I after transcription initiation. Inhibition of Ser170/172 phosphorylation or covalent tethering of TIF-IA to the RPA43 subunit of Pol I inhibits rDNA transcription, leading to perturbation of nucleolar structure and cell cycle arrest. Fluorescence recovery after photobleaching and chromatin immunoprecipitation experiments demonstrate that dissociation of TIF-IA from Pol I is a prerequisite for proper transcription elongation. In support of phosphorylation of TIF-IA switching from the initiation into the elongation phase, dephosphorylation of Ser170/172 by FCP1 facilitates the reassociation of TIF-IA with Pol I, allowing a new round of rDNA transcription. The results reveal a mechanism by which the functional interplay between CK2 and FCP1 sustains multiple rounds of Pol I transcription.

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 Targeting the RNA Polymerase I Transcription for Cancer Therapy Comes of Age

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 266 ◽  
Author(s):  
Rita Ferreira ◽  
John S. Schneekloth ◽  
Konstantin I. Panov ◽  
Katherine M. Hannan ◽  
Ross D. Hannan
Keyword(s):  
Rna Polymerase ◽  
Cancer Progression ◽  
Ribosome Biogenesis ◽  
Therapeutic Potential ◽  
Cancer Therapeutics ◽  
Active Role ◽  
Rna Polymerase I ◽  
Cancer Etiology ◽  
Pol I ◽  
Polymerase I

Transcription of the ribosomal RNA genes (rDNA) that encode the three largest ribosomal RNAs (rRNA), is mediated by RNA Polymerase I (Pol I) and is a key regulatory step for ribosomal biogenesis. Although it has been reported over a century ago that the number and size of nucleoli, the site of ribosome biogenesis, are increased in cancer cells, the significance of this observation for cancer etiology was not understood. The realization that the increase in rRNA expression has an active role in cancer progression, not only through increased protein synthesis and thus proliferative capacity but also through control of cellular check points and chromatin structure, has opened up new therapeutic avenues for the treatment of cancer through direct targeting of Pol I transcription. In this review, we discuss the rational of targeting Pol I transcription for the treatment of cancer; review the current cancer therapeutics that target Pol I transcription and discuss the development of novel Pol I-specific inhibitors, their therapeutic potential, challenges and future prospects.

scholarly journals Multiple Protein-Protein Interactions by RNA Polymerase I-Associated Factor PAF49 and Role of PAF49 in rRNA Transcription

2004 ◽  
Vol 24 (14) ◽  
pp. 6338-6349 ◽  
Author(s):  
Kazuo Yamamoto ◽  
Mika Yamamoto ◽  
Ken-ichi Hanada ◽  
Yasuhisa Nogi ◽  
Toshifumi Matsuyama ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase I ◽  
Rrna Synthesis ◽  
Associated Factor ◽  
Isolation And Characterization ◽  
Cell Extracts ◽  
Rrna Transcription ◽  
Pol I ◽  
Polymerase I

ABSTRACT We previously demonstrated the critical role of RNA polymerase I (Pol I)-associated factor PAF53 in mammalian rRNA transcription. Here, we report the isolation and characterization of another Pol I-associated factor, PAF49. Mouse PAF49 shows striking homology to the human nucleolar protein ASE-1, so that they are considered orthologues. PAF49 and PAF53 were copurified with a subpopulation of Pol I during purification from cell extracts. Physical association of PAF49 with Pol I was confirmed by a coimmunoprecipitation assay. PAF49 was shown to interact with PAF53 through its N-terminal segment. This region of PAF49 also served as the target for TAFI48, the 48-kDa subunit of selectivity factor SL1. Concomitant with this interaction, the other components of SL1 also coimmunoprecipitated with PAF49. Specific transcription from the mouse rRNA promoter in vitro was severely impaired by anti-PAF49 antibody, which was overcome by addition of recombinant PAF49 protein. Moreover, overexpression of a deletion mutant of PAF49 significantly reduced pre-rRNA synthesis in vivo. Immunolocalization analysis revealed that PAF49 accumulated in the nucleolus of growing cells but dispersed to nucleoplasm in growth-arrested cells. These results strongly suggest that PAF49/ASE-1 plays an important role in rRNA transcription.

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