scholarly journals Pseudouridines of tRNA Anticodon Stem-Loop Have Unexpected Role in Mutagenesis in Pseudomonas sp.

2020 ◽  
Vol 9 (1) ◽  
pp. 25
Author(s):  
Mari Tagel ◽  
Heili Ilves ◽  
Margus Leppik ◽  
Karl Jürgenstein ◽  
Jaanus Remme ◽  
...  
Keyword(s):  
Mutation Frequency ◽  
Cumulative Effect ◽  
Mutagenic Effect ◽  
Specific Response ◽  
Ros Scavenging ◽  
Cellular Functions ◽  
Genetic Studies ◽  
Stem Loop ◽  
Pseudouridine Synthases ◽  
Pseudomonas Species

Pseudouridines are known to be important for optimal translation. In this study we demonstrate an unexpected link between pseudouridylation of tRNA and mutation frequency in Pseudomonas species. We observed that the lack of pseudouridylation activity of pseudouridine synthases TruA or RluA elevates the mutation frequency in Pseudomonas putida 3 to 5-fold. The absence of TruA but not RluA elevates mutation frequency also in Pseudomonas aeruginosa. Based on the results of genetic studies and analysis of proteome data, the mutagenic effect of the pseudouridylation deficiency cannot be ascribed to the involvement of error-prone DNA polymerases or malfunctioning of DNA repair pathways. In addition, although the deficiency in TruA-dependent pseudouridylation made P. putida cells more sensitive to antimicrobial compounds that may cause oxidative stress and DNA damage, cultivation of bacteria in the presence of reactive oxygen species (ROS)-scavenging compounds did not eliminate the mutator phenotype. Thus, the elevated mutation frequency in the absence of tRNA pseudouridylation could be the result of a more specific response or, alternatively, of a cumulative effect of several small effects disturbing distinct cellular functions, which remain undetected when studied independently. This work suggests that pseudouridines link the translation machinery to mutation frequency.

scholarly journals Ribavirin Reveals a Lethal Threshold of Allowable Mutation Frequency for Hantaan Virus

2007 ◽  
Vol 81 (21) ◽  
pp. 11722-11729 ◽  
Author(s):  
Dong-Hoon Chung ◽  
Yanjie Sun ◽  
William B. Parker ◽  
Jeffrey B. Arterburn ◽  
Al Bartolucci ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Mutation Frequency ◽  
Mutagenic Effect ◽  
Hantaan Virus ◽  
Viral Population ◽  
Wild Type ◽  
Cdna Population ◽  
Viral Cdna ◽  
Dose Dependent Decrease ◽  
Relationship Of

ABSTRACT The broad spectrum of antiviral activity of ribavirin (RBV) lies in its ability to inhibit IMP dehydrogenase, which lowers cellular GTP. However, RBV can act as a potent mutagen for some RNA viruses. Previously we have shown a lack of correlation between antiviral activity and GTP repression for Hantaan virus (HTNV) and evidence for RBV's ability to promote error-prone replication. To further explore the mechanism of RBV, GTP levels, specific infectivity, and/or mutation frequency was measured in the presence of RBV, mycophenolic acid (MPA), selenazofurin, or tiazofurin. While all four drugs resulted in a decrease in the GTP levels and infectious virus, only RBV increased the mutation frequency of viral RNA (vRNA). MPA, however, could enhance RBV's mutagenic effect, which suggests distinct mechanisms of action for each. Therefore, a simple drop in GTP levels does not drive the observed error-prone replication. To further explore RBV's mechanism of action, we made a comprehensive analysis of the mutation frequency over several RBV concentrations. Of importance, we observed that the viral population reached a threshold after which mutation frequency did not correlate with a dose-dependent decrease in the level of vRNA, PFU, or [RTP]/[GTP] (where RTP is ribavirin-5′-triphosphate) over these same concentrations of RBV. Modeling of the relationship of mutation frequency and drug concentration showed an asymptotic relationship at this point. After this threshold, approximately 57% of the viral cDNA population was identical to the wild type. These studies revealed a lethal threshold, after which we did not observe a complete loss of the quasispecies structure of the wild-type genome, although we observed extinction of HTNV.

Mutational analysis of the HIS4 translational initiator region in Saccharomyces cerevisiae

1988 ◽  
Vol 8 (7) ◽  
pp. 2964-2975 ◽  
Author(s):  
A M Cigan ◽  
E K Pabich ◽  
T F Donahue
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mutational Analysis ◽  
Noncoding Region ◽  
Start Codon ◽  
General Mechanism ◽  
Sequence Context ◽  
Optimal Sequence ◽  
Genetic Studies ◽  
Stem Loop ◽  
Insertion Mutations

We have mutated various features of the 5' noncoding region of the HIS4 mRNA in light of established Saccharomyces cerevisiae and mammalian consensus translational initiator regions. Our analysis indicates that insertion mutations that introduce G + C-rich sequences in the leader, particularly those that result in stable stem-loop structures in the 5' noncoding region of the HIS4 message, severely affect translation initiation. Mutations that alter the length of the HIS4 leader from 115 to 39 nucleotides had no effect on expression, and sequence context changes both 5' and 3' to the HIS4 AUG start codon resulted in no more than a twofold decrease of expression. Changing the normal context at HIS4 5'-AAUAAUGG-3' to the optimal sequence context proposed for mammalian initiator regions 5'-CACCAUGG-3' did not result in stimulation of HIS4 expression. These studies, in conjunction with comparative and genetic studies in S. cerevisiae, support a general mechanism of initiation of protein synthesis as proposed by the ribosomal scanning model.

scholarly journals Integrin-linked kinase (ILK) and its interactors

2001 ◽  
Vol 155 (4) ◽  
pp. 505-510 ◽  
Author(s):  
Chuanyue Wu ◽  
Shoukat Dedhar
Keyword(s):  
Cell Biology ◽  
Cell Shape ◽  
Shape Change ◽  
Signaling Proteins ◽  
Cellular Functions ◽  
Genetic Studies ◽  
Contact Sites ◽  
Cell Shape Change ◽  
Cell Matrix ◽  
Integrin Linked Kinase

How intracellular cytoskeletal and signaling proteins connect and communicate with the extracellular matrix (ECM) is a fundamental question in cell biology. Recent biochemical, cell biological, and genetic studies have revealed important roles of cytoplasmic integrin-linked kinase (ILK) and its interactive proteins in these processes. Cell adhesion to ECM is an important process that controls cell shape change, migration, proliferation, survival, and differentiation. Upon adhesion to ECM, integrins and a selective group of cytoskeletal and signaling proteins are recruited to cell matrix contact sites where they link the actin cytoskeleton to the ECM and mediate signal transduction between the intracellular and extracellular compartments. In this review, we discuss the molecular activities and cellular functions of ILK, a protein that is emerging as a key component of the cell–ECM adhesion structures.

scholarly journals Mutational analysis of the HIS4 translational initiator region in Saccharomyces cerevisiae.

1988 ◽  
Vol 8 (7) ◽  
pp. 2964-2975 ◽  
Author(s):  
A M Cigan ◽  
E K Pabich ◽  
T F Donahue
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mutational Analysis ◽  
Noncoding Region ◽  
Start Codon ◽  
General Mechanism ◽  
Sequence Context ◽  
Optimal Sequence ◽  
Genetic Studies ◽  
Stem Loop ◽  
Insertion Mutations

We have mutated various features of the 5' noncoding region of the HIS4 mRNA in light of established Saccharomyces cerevisiae and mammalian consensus translational initiator regions. Our analysis indicates that insertion mutations that introduce G + C-rich sequences in the leader, particularly those that result in stable stem-loop structures in the 5' noncoding region of the HIS4 message, severely affect translation initiation. Mutations that alter the length of the HIS4 leader from 115 to 39 nucleotides had no effect on expression, and sequence context changes both 5' and 3' to the HIS4 AUG start codon resulted in no more than a twofold decrease of expression. Changing the normal context at HIS4 5'-AAUAAUGG-3' to the optimal sequence context proposed for mammalian initiator regions 5'-CACCAUGG-3' did not result in stimulation of HIS4 expression. These studies, in conjunction with comparative and genetic studies in S. cerevisiae, support a general mechanism of initiation of protein synthesis as proposed by the ribosomal scanning model.

scholarly journals Extracellular and subcellular regulation of the PI3K/Akt cassette: new mechanisms for controlling insulin and growth factor signalling

2007 ◽  
Vol 35 (2) ◽  
pp. 219-221 ◽  
Author(s):  
C. Wilson ◽  
N. Vereshchagina ◽  
B. Reynolds ◽  
D. Meredith ◽  
C.A.R. Boyd ◽  
...  
Keyword(s):  
Cellular Response ◽  
Human Cancer ◽  
Molecular Genetic ◽  
Cell Types ◽  
Cellular Functions ◽  
Genetic Studies ◽  
Downstream Effects ◽  
Growth Factor Signalling ◽  
Cell Type Specific ◽  
Phosphoinositide 3 Kinase

The PI3K (phosphoinositide 3-kinase)/Akt (also called protein kinase B) signalling cassette plays a central role in the response to growth factors, particularly insulin-like molecules, and its misregulation is a characteristic feature of diabetes and many forms of human cancer. Recent molecular genetic studies initiated in the fruitfly, Drosophila melanogaster, have highlighted two new cell-type-specific mechanisms regulating PI3K/Akt signalling and its downstream effects. First, the cellular response to this cassette is modulated by several classes of cell-surface transporters and sensors, suggesting an important role for extracellular nutrients in insulin-sensitivity. Secondly, various cell types show a markedly different subcellular distribution of the activated kinase Akt, influencing the cellular functions of this molecule. These findings reveal new mechanisms by which processes such as growth, lipogenesis and insulin resistance can be differentially regulated and may suggest novel strategies for treating insulin-linked diseases.

scholarly journals The oligomeric assembly of galectin-11 is critical for anti-parasitic activity in sheep (Ovis aries)

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Dhanasekaran Sakthivel ◽  
Sarah Preston ◽  
Robin B. Gasser ◽  
Tatiana P. Soares da Costa ◽  
Julia N. Hernandez ◽  
...  
Keyword(s):  
Selective Breeding ◽  
Inflammatory Responses ◽  
Gastrointestinal Nematodes ◽  
Ovis Aries ◽  
Parasitic Nematodes ◽  
Cellular Functions ◽  
Genetic Studies ◽  
Oligomeric Assembly ◽  
Parasitic Activity

AbstractGalectins are a family of glycan-binding molecules with a characteristic affinity for ß-D-glycosides that mediate a variety of important cellular functions, including immune and inflammatory responses. Galectin-11 (LGALS-11) has been recently identified as a mediator induced specifically in animals against gastrointestinal nematodes and can interfere with parasite growth and development. Here, we report that at least two natural genetic variants of LGALS-11 exist in sheep, and demonstrate fundamental differences in anti-parasitic activity, correlated with their ability to dimerise. This study improves our understanding of the role of galectins in the host immune and inflammatory responses against parasitic nematodes and provides a basis for genetic studies toward selective breeding of animals for resistance to parasites.

scholarly journals Role of Metabolism in Bone Development and Homeostasis

2020 ◽  
Vol 21 (23) ◽  
pp. 8992
Author(s):  
Akiko Suzuki ◽  
Mina Minamide ◽  
Chihiro Iwaya ◽  
Kenichi Ogata ◽  
Junichi Iwata
Keyword(s):  
Metabolic Pathways ◽  
Metabolic Diseases ◽  
Bone Cells ◽  
Bone Development ◽  
Bone Matrix ◽  
The Body ◽  
Cellular Functions ◽  
Genetic Studies ◽  
Cellular Dysfunction

Carbohydrates, fats, and proteins are the underlying energy sources for animals and are catabolized through specific biochemical cascades involving numerous enzymes. The catabolites and metabolites in these metabolic pathways are crucial for many cellular functions; therefore, an imbalance and/or dysregulation of these pathways causes cellular dysfunction, resulting in various metabolic diseases. Bone, a highly mineralized organ that serves as a skeleton of the body, undergoes continuous active turnover, which is required for the maintenance of healthy bony components through the deposition and resorption of bone matrix and minerals. This highly coordinated event is regulated throughout life by bone cells such as osteoblasts, osteoclasts, and osteocytes, and requires synchronized activities from different metabolic pathways. Here, we aim to provide a comprehensive review of the cellular metabolism involved in bone development and homeostasis, as revealed by mouse genetic studies.

scholarly journals Effect and Response of Quercus ilex subsp. ballota [Desf.] Samp. Seedlings From Three Contrasting Andalusian Populations to Individual and Combined Phytophthora cinnamomi and Drought Stresses

2021 ◽  
Vol 12 ◽  
Author(s):  
Bonoso San-Eufrasio ◽  
María Ángeles Castillejo ◽  
Mónica Labella-Ortega ◽  
Francisco J. Ruiz-Gómez ◽  
Rafael M. Navarro-Cerrillo ◽  
...  
Keyword(s):  
Quercus Ilex ◽  
Phytophthora Cinnamomi ◽  
Protein Profile ◽  
Specific Response ◽  
Proteomics Data ◽  
Ros Scavenging ◽  
Combined Stresses ◽  
Leaf Chlorosis ◽  
Leaf Chlorophyll Fluorescence ◽  
The Individual

Quercus ilex L. is the dominant species in the Mediterranean forest and agrosilvopastoral ecosystem “dehesa.” Currently, this forest species is threatened by natural and anthropogenic agents, especially by the decline syndrome, which is caused by Phytophthora cinnamomi and drought periods. Although the morphological and physiological responses of Q. ilex to combined stress (P. cinnamomi and drought) have been examined already, little is known at the molecular level. In this study, we studied the effect and response of 8-month seedlings from three contrasting Andalusian populations (Seville [Se], Granada [Gr], and Almeria [Al]) to the individual and combined stresses of P. cinnamomi and drought from morphological, physiological, biochemical, and proteomics data. Whereas, seedling damage (leaf chlorosis and necrosis) and mortality were greater under the combined stresses in the three populations, the effect of each individual stress was population-dependent. Resilient individuals were found in all the populations at different percentages. The decrease in leaf chlorophyll fluorescence, photosynthetic activity, and stomatal conductance observed in undamaged seedlings was greater in the presence of both stresses, the three populations responding similarly to drought and P. cinnamomi. Biochemical and proteomic analyses of undamaged seedlings from the two most markedly contrasting populations (Se and Al) revealed the absence of significant differences in the contents in photosynthetic pigments, amino acids, and phenolics among treatments. The Se and Al populations exhibited changes in protein profile in response to the different treatments, with 83 variable proteins in the former population and 223 in the latter. Variable proteins belonged to 16 different functional groups, the best represented among which were protein folding, sorting and degradation, carbohydrate, amino acid, and secondary metabolism, photosynthesis, and ROS scavenging. While photosynthetic proteins were mainly downaccumulated, those of stress-responsive were upaccumulated. Although no treatment-specific response was observed in any functional group, differences in abundance were especially marked under the combined stresses. The following variable proteins are proposed as putative markers for resilience in Q. ilex, namely, aldehyde dehydrogenase, glucose-6-phosphate isomerase, 50S ribosomal protein L5, and α-1,4-glucan-protein synthase [UDP-forming].

scholarly journals Autophagy wins the 2016 Nobel Prize in Physiology or Medicine: Breakthroughs in baker's yeast fuel advances in biomedical research

2016 ◽  
Vol 114 (2) ◽  
pp. 201-205 ◽  
Author(s):  
Beth Levine ◽  
Daniel J. Klionsky
Keyword(s):  
Nobel Prize ◽  
Genotoxic Stress ◽  
Cellular Functions ◽  
Nobel Committee ◽  
Genetic Studies ◽  
Cellular Survival ◽  
Pathogen Elimination ◽  
Wide Range ◽  
Health And Disease ◽  
Key Steps

Autophagy is an ancient pathway in which parts of eukaryotic cells are self-digested within the lysosome or vacuole. This process has been studied for the past seven decades; however, we are only beginning to gain a molecular understanding of the key steps required for autophagy. Originally characterized as a hormonal and starvation response, we now know that autophagy has a much broader role in biology, including organellar remodeling, protein and organelle quality control, prevention of genotoxic stress, tumor suppression, pathogen elimination, regulation of immunity and inflammation, maternal DNA inheritance, metabolism, and cellular survival. Although autophagy is usually a degradative pathway, it also participates in biosynthetic and secretory processes. Given that autophagy has a fundamental role in many essential cellular functions, it is not surprising that autophagic dysfunction is associated with a wide range of human diseases. Genetic studies in various fungi, particularlySaccharomyces cerevisiae, provided the key initial breakthrough that led to an explosion of research on the basic mechanisms and the physiological connections of autophagy to health and disease. The Nobel Committee has recognized this breakthrough by the awarding of the 2016 Nobel Prize in Physiology or Medicine for research in autophagy.

Sign in / Sign up

Export Citation Format

Share Document