scholarly journals The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Qi Zhang ◽  
Xiang Zhou ◽  
RuiZhi Wu ◽  
Amber Mosley ◽  
Shelya X Zeng ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
De Novo ◽  
Cancer Cell Growth ◽  
Nucleotide Biosynthesis ◽  
Imp Dehydrogenase ◽  
Dna And Rna ◽  
Dna And Rna Synthesis ◽  
P53 Activation ◽  
Ribosomal Stress

The ‘ribosomal stress (RS)-p53 pathway’ is triggered by any stressor or genetic alteration that disrupts ribosomal biogenesis, and mediated by several ribosomal proteins (RPs), such as RPL11 and RPL5, which inhibit MDM2 and activate p53. Inosine monophosphate (IMP) dehydrogenase 2 (IMPDH2) is a rate-limiting enzyme in de novo guanine nucleotide biosynthesis and crucial for maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. It is highly expressed in many malignancies. We previously showed that inhibition of IMPDH2 leads to p53 activation by causing RS. Surprisingly, our current study reveals that Inauzhin (INZ), a novel non-genotoxic p53 activator by inhibiting SIRT1, can also inhibit cellular IMPDH2 activity, and reduce the levels of cellular GTP and GTP-binding nucleostemin that is essential for rRNA processing. Consequently, INZ induces RS and the RPL11/RPL5-MDM2 interaction, activating p53. These results support the new notion that INZ suppresses cancer cell growth by dually targeting SIRT1 and IMPDH2.

The role of p53 in regulating genomic stability when DNA and RNA synthesis are inhibited

1995 ◽  
Vol 20 (10) ◽  
pp. 431-434 ◽  
Author(s):  
Olga B. Chernova ◽  
Michail V. Chernov ◽  
Munna L. Agarwal ◽  
William R. Taylor ◽  
George R. Stark
Keyword(s):  
Rna Synthesis ◽  
Genomic Stability ◽  
Dna And Rna ◽  
Dna And Rna Synthesis

scholarly journals Zinc Signaling in the Mammary Gland: For Better and for Worse

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1204
Author(s):  
Moumita Chakraborty ◽  
Michal Hershfinkel
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Cancer Progression ◽  
Cellular Level ◽  
Normal Mammary Gland ◽  
Dna And Rna ◽  
Dna And Rna Synthesis ◽  
Zinc Signaling ◽  
Epithelial Physiology

Zinc (Zn2+) plays an essential role in epithelial physiology. Among its many effects, most prominent is its action to accelerate cell proliferation, thereby modulating wound healing. It also mediates affects in the gastrointestinal system, in the testes, and in secretory organs, including the pancreas, salivary, and prostate glands. On the cellular level, Zn2+ is involved in protein folding, DNA, and RNA synthesis, and in the function of numerous enzymes. In the mammary gland, Zn2+ accumulation in maternal milk is essential for supporting infant growth during the neonatal period. Importantly, Zn2+ signaling also has direct roles in controlling mammary gland development or, alternatively, involution. During breast cancer progression, accumulation or redistribution of Zn2+ occurs in the mammary gland, with aberrant Zn2+ signaling observed in the malignant cells. Here, we review the current understanding of the role of in Zn2+ the mammary gland, and the proteins controlling cellular Zn2+ homeostasis and signaling, including Zn2+ transporters and the Gq-coupled Zn2+ sensing receptor, ZnR/GPR39. Significant advances in our understanding of Zn2+ signaling in the normal mammary gland as well as in the context of breast cancer provides new avenues for identification of specific targets for breast cancer therapy.

P53 is Activated without RPL11 Upregulation in Diamond-Blackfan Anemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3432-3432
Author(s):  
Hong-Yan Du ◽  
M. Tarek Elghetany ◽  
Blanche P Alter ◽  
Akiko Shimamura
Keyword(s):  
Bone Marrow ◽  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Mrna Levels ◽  
Protein Levels ◽  
Diamond Blackfan Anemia ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
P53 Activation ◽  
Ribosomal Stress

Abstract Abstract 3432 Diamond-Blackfan anemia (DBA) is an autosomal dominantly inherited bone marrow failure syndrome characterized by red cell aplasia, physical anomalies, and cancer predisposition. DBA is caused by mutations resulting in haploinsufficiency of genes encoding ribosomal proteins. p53 is activated in the erythroid lineage following reduction of ribosomal protein expression; however the mechanism whereby ribosomal stress results in p53 activation in DBA remains unclear. RPL11 has been proposed to play a central role in p53 activation following ribosomal stress. Reduced expression of individual small ribosomal subunit proteins in a tumor cell line resulted in increased translation of RPL11. Excess free RPL11 can bind and inactivate HDM2, an E3 ubiquitin ligase targeting p53 for degradation. The recent demonstration that cellular responses to ribosomal perturbations vary widely between different tissues raised the question of whether RPL11 upregulation contributes to p53 activation following ribosomal stress in hematopoietic progenitors. To address this question, we modeled DBA in human CD34+ cells. Since RPS19 is the most commonly mutated gene in DBA, we used lentiviral vectors expressing short hairpin RNAs to knock down RPS19 expression in primary human CD34+ cells. RPS19 protein levels were reduced to about 50% of control levels in a manner reflecting the haploinsufficient state in DBA. RPS19 depletion resulted in elevated p53 protein levels and increased mRNA levels of p21, a transcriptional target of p53. Total p53 mRNA levels and p53 mRNA translational activity remained unchanged consistent with a post-transcriptional mechanism for p53 activation. Although total RPL11 mRNA levels were not diminished following RPS19 depletion, RPL11 protein levels were significantly decreased consistent with post-transcriptional downregulation. Depletion of RPS19 in human CD34+ cells did not affect polysome loading of RPL11 mRNA. Reduction of additional ribosomal proteins also accompanied RPS19 knockdown consistent with coordinate regulation of multiple ribosomal protein levels. Corticosteroids, which improve anemia in the majority of DBA patients, did not prevent p53 activation, nor did this improve RPS19 or RPL11 protein levels. Expression of p53 was also assessed in bone marrow biopsy slides from 26 DBA patients with the following genotypes: RPS19 (18), RPS24 (2), RPS26 (2), RPS10 (1), RPS17 (1), RPS7 (1), and RPL11 (1). p53 was over-expressed in all but one patient (RPS26), and was clearly over-expressed in the DBA patient harboring the RPL11 mutation. In summary, we find that p53 activation in DBA does not require upregulation of RPL11 translation or elevated RPL11 protein levels. p53 activation persists in DBA caused by RPL11 deficiency. Corticosteroids do not improve ribosomal protein levels nor do they prevent p53 activation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Regulatory Role of the Bateman Domain of IMP Dehydrogenase in Adenylate Nucleotide Biosynthesis

2009 ◽  
Vol 284 (12) ◽  
pp. 7960-7969 ◽  
Author(s):  
Maxim Pimkin ◽  
Julia Pimkina ◽  
George D. Markham
Keyword(s):  
Regulatory Role ◽  
Nucleotide Biosynthesis ◽  
Imp Dehydrogenase

scholarly journals Comparative Genomic Analysis Reveals a Critical Role of De Novo Nucleotide Biosynthesis for Saccharomyces cerevisiae Virulence

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0122382 ◽  
Author(s):  
Roberto Pérez-Torrado ◽  
Silvia Llopis ◽  
Benedetta Perrone ◽  
Rocío Gómez-Pastor ◽  
Bernhard Hube ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
De Novo ◽  
Critical Role ◽  
Genomic Analysis ◽  
Comparative Genomic Analysis ◽  
Comparative Genomic ◽  
Nucleotide Biosynthesis

scholarly journals Author response: The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress

2014 ◽  
Author(s):  
Qi Zhang ◽  
Xiang Zhou ◽  
RuiZhi Wu ◽  
Amber Mosley ◽  
Shelya X Zeng ◽  
...  
Keyword(s):  
Author Response ◽  
Imp Dehydrogenase ◽  
Ribosomal Stress

scholarly journals Sequencing Enabling Design and Learning in Synthetic Biology

2020 ◽  
Author(s):  
Pierre-Aurelien Gilliot ◽  
Thomas E. Gorochowski
Keyword(s):  
Machine Learning ◽  
Synthetic Biology ◽  
De Novo ◽  
Data Sets ◽  
New Wave ◽  
Design Rules ◽  
Biological Design ◽  
Sequencing Technologies ◽  
Dna And Rna

The ability to read and quantify nucleic acids such as DNA and RNA using sequencing technologies has revolutionized our understanding of life. With the emergence of synthetic biology, these tools are now being put to work in new ways - enabling de novo biological design. Here, we show how sequencing is supporting the creation of a new wave of biological parts and systems, as well as providing the vast data sets needed for the machine learning of design rules for predictive bioengineering. However, we believe this is only the tip of the iceberg and end by providing an outlook on recent advances that will likely broaden the role of sequencing in synthetic biology and its deployment in real-world environments.

scholarly journals Stable isotope informed genome-resolved metagenomics reveals that Saccharibacteria utilize microbially processed plant derived carbon

2017 ◽  
Author(s):  
Evan P. Starr ◽  
Shengjing Shi ◽  
Steven J. Blazewicz ◽  
Alexander J. Probst ◽  
Donald J. Herman ◽  
...  
Keyword(s):  
Rhizosphere Soil ◽  
De Novo ◽  
Plant Root ◽  
Gradient Centrifugation ◽  
Isotopic Labeling ◽  
Building Blocks ◽  
Carbon Utilization ◽  
Nucleotide Synthesis ◽  
Dna And Rna ◽  
Dna And Rna Synthesis

AbstractBackgroundThe transformation of plant photosynthate into soil organic carbon and its recycling to CO2 by soil microorganisms is one of the central components of the terrestrial carbon cycle. There are currently large knowledge gaps related to which soil-associated microorganisms take up plant carbon in the rhizosphere and the fate of that carbon.ResultsWe conducted an experiment in which common wild oats (Avena fatua) were grown in a 13CO2 atmosphere and the rhizosphere and non-rhizosphere soil was sampled for genomic analyses. Density gradient centrifugation of DNA extracted from soil samples enabled distinction of microbes that did and did not incorporate the 13C into their DNA. A 1.45 Mbp genome of a Saccharibacteria (TM7) was identified and, despite the microbial complexity of rhizosphere soil, curated to completion. The genome lacks many biosynthetic pathways, including genes required to synthesize DNA de novo. Rather, it requires externally-derived nucleotides for DNA and RNA synthesis. Given this, we conclude that rhizosphere-associated Saccharibacteria recycle DNA from bacteria that live off plant exudates and/or phage that acquired 13C because they preyed upon these bacteria and/or directly from the labelled plant DNA. Isotopic labeling indicates that the population was replicating during the six-week period of plant growth. Interestingly, the genome is ~30% larger than other complete Saccharibacteria genomes from non-soil environments, largely due to more genes for complex carbon utilization and amino acid metabolism. Given the ability to degrade cellulose, hemicellulose, pectin, starch and 1,3-β-glucan, we predict that this Saccharibacteria generates energy by fermentation of soil necromass and plant root exudates to acetate or lactate. The genome encodes a linear electron transport chain featuring a terminal oxidase, suggesting that this Saccharibacteria may respire aerobically. The genome encodes a hydrolase that could breakdown salicylic acid, a plant defense signaling molecule, and genes to make a variety of isoprenoids, including the plant hormone zeatin.ConclusionsRhizosphere Saccharibacteria likely depend on other bacteria for basic cellular building blocks. We propose that isotopically labeled CO2 is incorporated into plant-derived carbon and then into the DNA of rhizosphere organisms capable of nucleotide synthesis, and the nucleotides are recycled into Saccharibacterial genomes.

scholarly journals Unravelling the virome in birch: RNA-Seq reveals a complex of known and novel viruses

2019 ◽  
Author(s):  
Artemis Rumbou ◽  
Thierry Candresse ◽  
Armelle Marais ◽  
Laurence Svanella-Dumas ◽  
Maria Landgraf ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
De Novo ◽  
Leaf Roll ◽  
Viral Population ◽  
Comprehensive Overview ◽  
Dna And Rna ◽  
Birch Trees ◽  
Viral Communities ◽  
The Impact

AbstractHigh-throughput sequencing (HTS), combined with bioinformatics for de novo discovery and assembly of plant virus or viroid genome reads, has promoted the discovery of abundant novel DNA and RNA viruses and viroids. However, the elucidation of a viral population in a single plant is rarely reported. In five birch trees of German and Finnish origin exhibiting symptoms of birch leaf-roll disease (BRLD), we identified in total five viruses, among which three are novel. The number of identified virus variants in each transcriptome ranged from one to five. The novel species are genetically - fully or partially - characterized, they belong to the genera Carlavirus, Idaeovirus and Capillovirus and they are tentatively named birch carlavirus, birch idaeovirus, and birch capillovirus, respectively. The only virus systematically detected by HTS in symptomatic trees affected by the BRLD was the recently discovered birch leafroll-associated virus. The role of the new carlavirus in BLRD etiology seems at best weak, as it was detected only in one of three symptomatic trees. Continuing studies have to clarify the impact of the carlavirus to the BLRD. The role of the Capillovirus and the Idaeovirus within the BLRD complex and whether they influence plant vitality need to be investigated. Our study reveals the viral population in single birch trees and provides a comprehensive overview for the diversities of the viral communities they harbor.

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