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Jack Greenblatt - One of the best experts on this subject based on the ideXlab platform.
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recognition of boxa antiterminator rna by the e coli antitermination factors nusb and Ribosomal Protein s10
1993Co-Authors: Justin R. Nodwell, Jack GreenblattAbstract:Abstract The boxA sequences of the E. coli Ribosomal RNA ( rrn ) operons are sufficient to cause RNA polymerase to read through Rho-dependent transcriptional terminators. We show that a complex of the transcription antitermination factors NusB and Ribosomal Protein S10 interacts specifically with boxA RNA. Neither NusB nor S10 binds boxA RNA on its own, and neither NusA nor NusG affects the interaction of the NusB-S10 complex with boxA RNA. Mutations in boxA that impair its antitermination activity compromise its interaction with NusB and S10, suggesting that Ribosomal Protein S10 regulates the synthesis of Ribosomal RNA in bacteria. RNA containing the closely related boxA sequence from the bacteriophage λ nutR site is not stably bound by NusB and S10. This probably explains why antitermination in phage λ depends on the phage λ N Protein and the boxB component of the nut site, in addition to boxA .
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direct interaction between two escherichia coli transcription antitermination factors nusb and Ribosomal Protein s10
1992Co-Authors: Stephen W Mason, Joyce Li, Jack GreenblattAbstract:Abstract The Escherichia coli Proteins NusB and Ribosomal Protein S10 are important for transcription antitermination by the bacteriophage lambda N Protein. We have used sucrose gradient co-sedimentation and affinity chromatography with immobilized Ribosomal Protein S10, a glutathione S-transferase-S10 fusion Protein, and NusB to show that NusB binds directly and very selectively to S10. The interaction is non-ionic and has an estimated K d value of 10 −7 m . We hypothesize that NusB binds to N-modified transcription complexes primarily by interacting with S10.
Rajendra K Agrawal - One of the best experts on this subject based on the ideXlab platform.
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interaction of the g domain of elongation factor g and the c terminal domain of Ribosomal Protein l7 l12 during translocation as revealed by cryo em
2005Co-Authors: Partha P Datta, Manjuli R Sharma, Joachim Frank, Rajendra K AgrawalAbstract:During tRNA translocation on the ribosome, an arc-like connection (ALC) is formed between the G' domain of elongation factor G (EF-G) and the L7/L12-stalk base of the large Ribosomal subunit in the GDP state. To delineate the boundary of EF-G within the ALC, we tagged an amino acid residue near the tip of the G' domain of EF-G with undecagold, which was then visualized with three-dimensional cryo-electron microscopy (cryo-EM). Two distinct positions for the undecagold, observed in the GTP-state and GDP-state cryo-EM maps of the ribosome bound EF-G, allowed us to determine the movement of the labeled amino acid. Molecular analyses of the cryo-EM maps show: (1) that three structural components, the N-terminal domain of Ribosomal Protein L11, the C-terminal domain of Ribosomal Protein L7/L12, and the G' domain of EF-G, participate in formation of the ALC; and (2) that both EF-G and the Ribosomal Protein L7/L12 undergo large conformational changes to form the ALC.
Steven R Ellis - One of the best experts on this subject based on the ideXlab platform.
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deletion of Ribosomal Protein genes is a common vulnerability in human cancer especially in concert with tp53 mutations
2017Co-Authors: Ram Ajore, David M Raiser, Marie Mcconkey, Magnus Joud, Bernd Boidol, Brenton G Mar, Gordon Saksena, David M Weinstock, Scott A Armstrong, Steven R EllisAbstract:Heterozygous inactivating mutations in Ribosomal Protein genes (RPGs) are associated with hematopoietic and developmental abnormalities, activation of p53, and altered risk of cancer in humans and model organisms. Here we performed a large‐scale analysis of cancer genome data to examine the frequency and selective pressure of RPG lesions across human cancers. We found that hemizygous RPG deletions are common, occurring in about 43% of 10,744 cancer specimens and cell lines. Consistent with p53‐dependent negative selection, such lesions are underrepresented in TP53 ‐intact tumors ( P ≪ 10−10), and shRNA‐mediated knockdown of RPGs activated p53 in TP53 ‐wild‐type cells. In contrast, we did not see negative selection of RPG deletions in TP53 ‐mutant tumors. RPGs are conserved with respect to homozygous deletions, and shRNA screening data from 174 cell lines demonstrate that further suppression of hemizygously deleted RPGs inhibits cell growth. Our results establish RPG haploinsufficiency as a strikingly common vulnerability of human cancers that associates with TP53 mutations and could be targetable therapeutically. ![][1] Hemizygous deletion of Ribosomal Protein genes (RPGs) is a strikingly common vulnerability of human cancers that associates with TP53 mutations and could be targetable therapeutically. [1]: /embed/graphic-1.gif
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Ribosomal Protein sa haploinsufficiency in humans with isolated congenital asplenia
2013Co-Authors: Steven R Ellis, Alexandre Bolze, Nizar Mahlaoui, Minji Byun, Bridget Turner, Nikolaus S Trede, Avinash Abhyankar, Yuval Itan, Etienne PatinAbstract:Isolated congenital asplenia (ICA) is characterized by the absence of a spleen at birth in individuals with no other developmental defects. The patients are prone to life-threatening bacterial infections. The unbiased analysis of exomes revealed heterozygous mutations in RPSA in 18 patients from eight kindreds, corresponding to more than half the patients and over one-third of the kindreds studied. The clinical penetrance in these kindreds is complete. Expression studies indicated that the mutations carried by the patients-a nonsense mutation, a frameshift duplication, and five different missense mutations-cause autosomal dominant ICA by haploinsufficiency. RPSA encodes Ribosomal Protein SA, a component of the small subunit of the ribosome. This discovery establishes an essential role for RPSA in human spleen development.
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Ribosomal Protein gene deletions in diamond blackfan anemia
2011Co-Authors: Jason E Farrar, Jeffrey M. Lipton, Adrianna Vlachos, Eva Atsidaftos, Hannah Carlsondonohoe, Thomas C Markello, Robert J Arceci, Steven R Ellis, David M BodineAbstract:Diamond-Blackfan anemia (DBA) is a congenital BM failure syndrome characterized by hypoproliferative anemia, associated physical abnormalities, and a predisposition to cancer. Perturbations of the ribosome appear to be critically important in DBA; alterations in 9 different Ribosomal Protein genes have been identified in multiple unrelated families, along with rarer abnormalities of additional Ribosomal Proteins. However, at present, only 50% to 60% of patients have an identifiable genetic lesion by Ribosomal Protein gene sequencing. Using genome-wide single-nucleotide polymorphism array to evaluate for regions of recurrent copy variation, we identified deletions at known DBA-related Ribosomal Protein gene loci in 17% (9 of 51) of patients without an identifiable mutation, including RPS19, RPS17, RPS26, and RPL35A. No recurrent regions of copy variation at novel loci were identified. Because RPS17 is a duplicated gene with 4 copies in a diploid genome, we demonstrate haploinsufficient RPS17 expression and a small subunit Ribosomal RNA processing abnormality in patients harboring RPS17 deletions. Finally, we report the novel identification of variable mosaic loss involving known DBA gene regions in 3 patients from 2 kindreds. These data suggest that Ribosomal Protein gene deletion is more common than previously suspected and should be considered a component of the initial genetic evaluation in cases of suspected DBA.
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derivatives of the yeast mitochondrial Ribosomal Protein mrps28 replace Ribosomal Protein s15 as functional components of the escherichia coli ribosome
1993Co-Authors: Mary O Huff, Pamela J Hanicjoyce, Steven R EllisAbstract:Abstract The mitochondrial Ribosomal Protein MrpS28 is considerably larger than its eubacterial homolog, Escherichia coli Ribosomal Protein S15 (Eco S15). Relative to a region of homology that spans the entire length of the bacterial Protein, mature MrpS28 is extended by 117 and 48 amino acids at its amino and carboxyl termini, respectively. Both the amino-terminal and S15-like domains of MrpS28 are essential for function in yeast mitochondria. Here, we show that these same two domains function in E. coli. The S15-like domain of MrpS28 alone complements a cold sensitive mutation in E. coli strain KR121 that gives rise to reduced levels of Eco S15. However, complementation by the S15-like domain of MrpS28 is inefficient when compared with Eco S15. Surprisingly, the amino-terminal domain of MrpS28, which is apparently a unique component of the mitochondrial ribosome and is unable by itself to complement the cold-sensitive phenotype, enhances the ability of the S15-like domain to support growth of KR121 cells at, nonpermissive temperatures. Together, these data suggest that the amino terminal domain contributes to the fundamental properties of MrpS28 involved in the assembly and function of both mitochondrial and E. coli ribosomes.
Adrianna Vlachos - One of the best experts on this subject based on the ideXlab platform.
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Ribosomal Protein gene deletions in diamond blackfan anemia
2011Co-Authors: Jason E Farrar, Jeffrey M. Lipton, Adrianna Vlachos, Eva Atsidaftos, Hannah Carlsondonohoe, Thomas C Markello, Robert J Arceci, Steven R Ellis, David M BodineAbstract:Diamond-Blackfan anemia (DBA) is a congenital BM failure syndrome characterized by hypoproliferative anemia, associated physical abnormalities, and a predisposition to cancer. Perturbations of the ribosome appear to be critically important in DBA; alterations in 9 different Ribosomal Protein genes have been identified in multiple unrelated families, along with rarer abnormalities of additional Ribosomal Proteins. However, at present, only 50% to 60% of patients have an identifiable genetic lesion by Ribosomal Protein gene sequencing. Using genome-wide single-nucleotide polymorphism array to evaluate for regions of recurrent copy variation, we identified deletions at known DBA-related Ribosomal Protein gene loci in 17% (9 of 51) of patients without an identifiable mutation, including RPS19, RPS17, RPS26, and RPL35A. No recurrent regions of copy variation at novel loci were identified. Because RPS17 is a duplicated gene with 4 copies in a diploid genome, we demonstrate haploinsufficient RPS17 expression and a small subunit Ribosomal RNA processing abnormality in patients harboring RPS17 deletions. Finally, we report the novel identification of variable mosaic loss involving known DBA gene regions in 3 patients from 2 kindreds. These data suggest that Ribosomal Protein gene deletion is more common than previously suspected and should be considered a component of the initial genetic evaluation in cases of suspected DBA.
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Ribosomal Protein genes rps10 and rps26 are commonly mutated in diamond blackfan anemia
2010Co-Authors: Leana Doherty, Mee Rie Sheen, Adrianna Vlachos, Valerie Choesmel, Mariefrancoise Odonohue, Catherine Clinton, Hal E SchneiderAbstract:Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in ∼30%–50% of patients. DBA has been associated with mutations in seven Ribosomal Protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 Ribosomal Protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the Proteins in rRNA processing.
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Ribosomal Protein S24 Gene Is Mutated in Diamond-Blackfan Anemia
2006Co-Authors: Hanna T. Gazda, Jeffrey M. Lipton, Adrianna Vlachos, Hal E Schneider, Sarah E. Ball, Eva Atsidaftos, Agnieszka Grabowska, Lilia B. Merida-long, Elzbieta Latawiec, Karen A. OrfaliAbstract:Diamond-Blackfan anemia (DBA) is a rare congenital red-cell aplasia characterized by anemia, bone-marrow erythroblastopenia, and congenital anomalies and is associated with heterozygous mutations in the Ribosomal Protein (RP) S19 gene (RPS19) in approximately 25% of probands. We report identification of de novo nonsense and splice-site mutations in another RP, RPS24 (encoded by RPS24 [10q22-q23]) in approximately 2% of RPS19 mutation-negative probands. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other RP or associated genes that lead to disrupted Ribosomal biogenesis and/or function may also cause DBA.
Avigail Dreazen - One of the best experts on this subject based on the ideXlab platform.
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Ribosomal Protein s6 kinase activity controls the ribosome biogenesis transcriptional program
2014Co-Authors: C Chauvin, Vonda Koka, A Nouschi, Virginie Mieulet, C Hoareauaveilla, Avigail DreazenAbstract:Ribosomal Protein S6 kinase activity controls the ribosome biogenesis transcriptional program
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Ribosomal Protein s6 kinase from top mrnas to cell size
2009Co-Authors: Oded Meyuhas, Avigail DreazenAbstract:Abstract Ribosomal Protein S6 kinase (S6K) has been implicated in the phosphorylation of multiple substrates and is subject to activation by a wide variety of signals that converge at mammalian target of rapamycin (mTOR). In the course of the search for its physiological role, it was proposed that S6K activation and Ribosomal Protein S6 (rpS6) phosphorylation account for the translational activation of a subgroup of transcripts, the TOP mRNAs. The structural hallmark of these mRNAs is an oligopyrimidine tract at their 5′-terminus, known as the 5′-TOP motif. TOP mRNAs consists of about 90 members that encode multiple components of the translational machinery, such as Ribosomal Proteins and translation factors. The translation efficiency of TOP mRNAs indeed correlates with S6K activation and rpS6 phosphorylation, yet recent biochemical and genetic studies have established that, although S6K and TOP mRNAs respond to similar signals and are regulated by mTOR, they maintain no cause and effect relationship. Instead, S6K is primarily involved in regulation of cell size, and affects glucose homeostasis, but is dispensable for global Protein synthesis, whereas translational efficiency of TOP mRNAs is a determinant of the cellular Protein synthesis capacity. Despite extensive studies of their function and mode of regulation, the mechanism underlying the effect of S6K on the cell size, as well as the trans -acting factor that mediates the translational control of TOP mRNAs, still await their identification.
