TIF-IA: An oncogenic target of pre-ribosomal RNA synthesis
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ribosome biogenesis
RNA polymerase I
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Ribosome biogenesis includes the making and processing of ribosomal RNAs, the biosynthesis of ribosomal proteins from their mRNAs in the cytosol and their transport to the nucleolus to assemble pre-ribosomal particles. Several stresses including cellular senescence reduce nucleolar rRNA synthesis and maturation increasing the availability of ribosome-free ribosomal proteins. Several ribosomal proteins can activate the p53 tumor suppressor pathway but cells without p53 can still arrest their proliferation in response to an imbalance between ribosomal proteins and mature rRNA production. Recent results on senescence-associated ribogenesis defects (SARD) show that the ribosomal protein S14 (RPS14 or uS11) can act as a CDK4/6 inhibitor linking ribosome biogenesis defects to the main engine of cell cycle progression. This work offers new insights into the regulation of the cell cycle and suggests novel avenues to design anticancer drugs.
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Ribosomes are vital for cell growth and survival. Until recently, it was believed that mutations in ribosomes or ribosome biogenesis factors would be lethal, due to the essential nature of these complexes. However, in the last few decades, a number of diseases of ribosome biogenesis have been discovered. It remains a challenge in the field to elucidate the molecular mechanisms underlying them.
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The hot tritium bombardment technique [(1976) Dokl. Akad. Nauk SSSR 228, 1237-1238] was used for studying the surface localization of ribosomal proteins on Escherichia coli ribosomes. The degree of tritium labeling of proteins was considered as a measure of their exposure (surface localization). Proteins S1, S4, S7, S9 and/or S11, S12 and/or L20, S13, S18, S20, S21, L5, L6, L7/L12, L10, L11, L16, L17, L24, L26 and L27 were shown to be the most exposed on the ribosome surface. The sets of exposed ribosomal proteins on the surface of 70 S ribosomes, on the one hand, and the surfaces of 50 S and 30 S ribosomal subunits in the dissociated state, on the other, were compared. It was found that the dissociation of ribosomes into subunits did not result in exposure of additional ribosomal proteins. The conclusion was drawn that proteins are absent from the contacting surfaces of the ribosomal subunits.
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ribosome biogenesis
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This review deals with results of affinity labelling experiments on proteins of the peptidyl-transferase centre (PTC) of animal ribosomes. From the studies it is concluded that ribosomal proteins L 5, L 21/23, L 32/33, and L 36 are the main candidates for the ribosomal P site and proteins L 6, L 18a, and L 28/29 for the ribosomal A site. Proteins L 10 and L 13/15 seem to be located in a more central region of the PTC. These findings are correlated with results obtained so far by using other techniques. Finally, the data are discussed, and a tentative model on the relative spatial arrangement of certain ribosomal proteins at the PTC is proposed.
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An unexpected degree of heterogeneity for the ribosomal proteins of E. coli was initially demonstrated by Waller (1964). Definitive verification of the multiplicity of ribosomal proteins has been obtained in several laboratories through the purification and characterization of the individual proteins (Kaltschmidt et al., 1967; Fogel and Sypherd, 1968; Moore et al., 1968; Hardy et al., 1969; Craven et al., 1969). There are approximately 50 different proteins in the ribosomes of E. coli. Although it is possible to demonstrate the functional contribution of individual ribosomal proteins (Traub et al., 1967), the presence of so many different proteins in the ribosome is quite inexplicable. This is a good index of how little is understood about the mechanism of protein synthesis.
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Ribosomal proteins have long been known to serve critical roles in facilitating the biogenesis of the ribosome and its ability to synthesize proteins. However, evidence is emerging that suggests ribosomal proteins are also capable of performing tissue-restricted, regulatory functions that impact normal development and pathological conditions, including cancer. The challenge in studying such regulatory functions is that elimination of many ribosomal proteins also disrupts ribosome biogenesis and/or function. Thus, it is difficult to determine whether developmental abnormalities resulting from ablation of a ribosomal protein result from loss of core ribosome functions or from loss of the regulatory function of the ribosomal protein. Rpl22, a ribosomal protein component of the large 60S subunit, provides insight into this conundrum; Rpl22 is dispensable for both ribosome biogenesis and protein synthesis yet its ablation causes tissue-restricted disruptions in development. Here we review evidence supporting the regulatory functions of Rpl22 and other ribosomal proteins
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5S ribosomal RNA
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