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Transcriptionally Regulatory Sequences of Phylogenetic Significance
Published in S. K. Dutta, DNA Systematics, 2019
Several factors for RNA polymerase I transcription in vitro have been identified245 and have been shown to be species specific. Human, mouse, and protozoan ribosomal DNAs are accurately transcribed in vitro only if cellular components from a homologous source are provided. Four major components have been characterized chromatographically: fraction A enhances transcription, B suppresses random initiation, C contains most of the polymerase, and D is indispensable for accurate initiation (see Reference 73).
Nuclear Protein Kinases
Published in Lubomir S. Hnilica, Chromosomal Nonhistone Proteins, 2018
Samuel J. Mitchell, Lewis J. Kleinsmith
Over the years there have been numerous reports of the presence of both phosphorylated nonhistone proteins and protein kinase activity in isolated nucleoli.70,73,80,101,102,156–172 Recently Kuehn and associates170–172 have made a significant breakthrough in this area by isolating a dimeric phosphoprotein of 139,000 mol wt that appears to be involved in the control of ribosomal RNA synthesis. This protein, which has been purified without the use of strong dissociating agents from nuclei of the slime mold Physarum polycephalum, stimulates RNA polymerase I-catalyzed synthesis of ribosomal RNA using a homologous nucleolar deoxyribonucleoprotein complex as template. The phosphoprotein binds selectively to those restriction fragments of nucleolar DNA which contain the symmetry axis of the palindromic ribosomal DNA. After removal of the phosphate groups from the protein by treatment with alkaline phosphatase, both binding to ribosomal DNA and the ability to stimulate ribosomal RNA synthesis are inhibited, suggesting that the phosphorylation state of this phosphoprotein may be controlling ribosomal gene transcription.
The Cell and Cell Division
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Packaging of ribosomal RNA occurs in the nucleolus, in which we find several large loops of DNA containing the tandem repeats for rRNA, which are known as nucleolar organizer regions. Here rRNA is transcribed by RNA polymerase I.
Ribosomopathies and cancer: pharmacological implications
Published in Expert Review of Clinical Pharmacology, 2022
Gazmend Temaj, Sarmistha Saha, Shpend Dragusha, Valon Ejupi, Brigitta Buttari, Elisabetta Profumo, Lule Beqa, Luciano Saso
Ribosome biogenesis begins with rRNA synthesis in the nucleolus, and the first step involves the formation of a preinitiation complex (PIC) around the rDNA promoter region. During ribosome biogenesis, RNA polymerase I (Pol I) is shown to transcribe rRNA genes into a single polycistronic transcript that is cleaved into 18S, 5.8S, and 28S rRNAs. During processing, many small nucleolar ribonucleoparticles (snoRNP) facilitate the modification of numerous rRNA residues [29,30], such as pseudouridylation and methylation (M), which plays pivotal roles in ribosomal maturation. These RNA transcripts in 5’ site form the 90S ‘processome’ complex. This complex 90S was cleaved to form pre-40S and 60S particles. In the nucleoplasm, RNA polymerase II (Pol II) and RNA polymerase III (Pol III) are involved in the transcription of the ribosomal protein (RPs) and 5S rRNA genes [31]. (Figure 1). Ribosomal proteins (RPs) after that are shown to stabilize small and large subunits, rRNA processing, pre-ribosome transport, RNA folding, and interaction of other factors that are required for ribosome synthesis or translation [32]. The RNA splicing process is very complex and has been described by many authors (see reviews by Watkins and Bohnsack [33], Lafontaine [290], and Rahhal and Seto [291].
Investigational drugs for the treatment of diffuse large B-cell lymphoma
Published in Expert Opinion on Investigational Drugs, 2021
Andrea Patriarca, Gianluca Gaidano
Ribosomes are fundamental for growth and proliferation both in normal cells and in cancerous cells. Their biogenesis is strictly related to the transcription of ribosomal RNA and so ultimately to the activity of RNA Polymerase I (Pol I). The activity of Pol I is regulated by different pathways such as RAS, MYC, and PI3K, which can be deregulated in DLBCL, making the inhibition of Pol I a logical therapeutic strategy [54–57]. CX-5461 is a small-molecule inhibitor of Pol I transcription, which, inhibiting rDNA transcription, elicits apoptosis through the nucleolar stress pathway in a p53 dependent or independent manner [58]. In a phase I study, 16 patients, including four R/R DLBCL, received CX-5461 [58]. The best ORR was stable disease in 2 out of 4 DLBCL. The drug was well tolerated with exclusively cutaneous AEs.
The role of mTOR in age-related diseases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Zofia Chrienova, Eugenie Nepovimova, Kamil Kuca
In addition, the synthesis of rRNAs and tRNAs is positively controlled by mTORC1. Mammalian RNA Polymerase I (Pol I) transcribes precursor rRNA that sequentially forms three out of four mature rRNA species (5.8S, 18S, and 28S), while RNA Polymerase III (Pol III) transcribes the fourth RNA species, 5S rRNA, as well as tRNA. Pol I can be activated by the mTORC1 effector S6K1 or by the mTORC1-mediated phosphorylation of transcription initiation factor IA (TIF1A), which is then translocated to the nucleolus, where it can activate Pol I44,45. mTORC1 also phosphorylates (and consequently inhibits) the repressor of RNA polymerase III transcription MAF1 homolog (MAF1)46. Moreover, the direct binding of mTORC1 to the promoter region of Pol I and Pol III increases gene expression47.