scholarly journals The Identification of Genetic Determinants of Methanol Tolerance in Yeast Suggests Differences in Methanol and Ethanol Toxicity Mechanisms and Candidates for Improved Methanol Tolerance Engineering

2021 ◽  
Vol 7 (2) ◽  
pp. 90
Author(s):  
Marta N. Mota ◽  
Luís C. Martins ◽  
Isabel Sá-Correia
Keyword(s):  
Dna Repair ◽  
Regulatory Networks ◽  
Fatty Acid Biosynthesis ◽  
Methylotrophic Yeast ◽  
Genetic Determinants ◽  
Methanol Tolerance ◽  
Yeast Strains ◽  
Starting Point ◽  
Ethanol Toxicity ◽  
Mutant Collection

Methanol is a promising feedstock for metabolically competent yeast strains-based biorefineries. However, methanol toxicity can limit the productivity of these bioprocesses. Therefore, the identification of genes whose expression is required for maximum methanol tolerance is important for mechanistic insights and rational genomic manipulation to obtain more robust methylotrophic yeast strains. The present chemogenomic analysis was performed with this objective based on the screening of the Euroscarf Saccharomyces cerevisiae haploid deletion mutant collection to search for susceptibility phenotypes in YPD medium supplemented with 8% (v/v) methanol, at 35 °C, compared with an equivalent ethanol concentration (5.5% (v/v)). Around 400 methanol tolerance determinants were identified, 81 showing a marked phenotype. The clustering of the identified tolerance genes indicates an enrichment of functional categories in the methanol dataset not enriched in the ethanol dataset, such as chromatin remodeling, DNA repair and fatty acid biosynthesis. Several genes involved in DNA repair (eight RAD genes), identified as specific for methanol toxicity, were previously reported as tolerance determinants for formaldehyde, a methanol detoxification pathway intermediate. This study provides new valuable information on genes and potential regulatory networks involved in overcoming methanol toxicity. This knowledge is an important starting point for the improvement of methanol tolerance in yeasts capable of catabolizing and copying with methanol concentrations present in promising bioeconomy feedstocks, including industrial residues.

scholarly journals Genome-Wide Association Study Reveals Novel Genetic Determinants of DNA Repair Capacity in Lung Cancer

2012 ◽  
Vol 73 (1) ◽  
pp. 256-264 ◽  
Author(s):  
Li-E Wang ◽  
Olga Y. Gorlova ◽  
Jun Ying ◽  
Yawei Qiao ◽  
Shih-Feng Weng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Repair ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genetic Determinants ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Genome Wide

scholarly journals High-throughput generation and phenotypic characterization of zebrafish CRISPR mutants of DNA repair genes

2020 ◽  
Author(s):  
Unbeom Shin ◽  
Khriezhanuo Nakhro ◽  
Chang-Kyu Oh ◽  
Blake Carrington ◽  
Hayne Song ◽  
...  
Keyword(s):  
Dna Repair ◽  
High Throughput ◽  
Phenotypic Characterization ◽  
Normal Brain ◽  
Dna Repair Genes ◽  
Loss Of Function ◽  
Repair Genes ◽  
Six Genes ◽  
Mutant Collection

ABSTRACTA systematic knowledge of the roles of DNA repair genes at the level of the organism has been limited due to the lack of appropriate experimental techniques. Here, we generated zebrafish loss-of-function mutants for 32 DNA repair and replication genes through multiplexed CRISPR/Cas9-mediated mutagenesis. High-throughput phenotypic characterization of our mutant collection revealed that three genes (atad5a, ddb1, pcna) are essential for proper embryonic development and hematopoiesis; seven genes (apex1, atrip, ino80, mre11a, shfm1, telo2, wrn) are required for growth and development during juvenile stage and six genes (blm, brca2, fanci, rad51, rad54l, rtel1) play critical roles in sex development. Furthermore, mutation in six genes (atad5a, brca2, polk, rad51, shfm1, xrcc1) displayed hypersensitivity to DNA damage agents. Further characterization of atad5a−/− mutants demonstrate that Atad5a is required for normal brain development and hematopoiesis. Our zebrafish mutant collection provides a unique resource for understanding of the roles of DNA repair genes at the organismal level.

scholarly journals Retinoblastoma: Magnetic Isotope Effects Might Make a Difference in the Current Anti-Cancer Research Strategy

2017 ◽  
Vol 60 (2) ◽  
pp. 93-96 ◽  
Author(s):  
Alexander A. Bukhvostov ◽  
Anton S. Dvornikov ◽  
Kirill V. Ermakov ◽  
Pavel B. Kurapov ◽  
Dmitry A. Kuznetsov
Keyword(s):  
Dna Repair ◽  
Isotope Effects ◽  
Research Strategy ◽  
Magnetic Isotope ◽  
Retinoblastoma Cells ◽  
Starting Point ◽  
Anti Cancer ◽  
Human Retinoblastoma ◽  
Associated Proteins ◽  
Species Being

Human retinoblastoma cells were proven to possess some very unusual DNApolβ species. Being 23.5 kDa monomers, which itself is not common for the DNApolβ superfamily members, these chromatin associated proteins manifests most of the DNApolβ-specifc functional peculiarities making them legitimate targets for DNA repair cytostatic inhibitors. Particularly, these tumor specific enzymes were found to be very sensitive to25Mg2+-,43Ca2+- and67Zn2+-promoted magnetic isotope effects (MIE) caused a marked DNA sequence growth limitation as well as a formation of the size-invalid, i.e. too short in length, DNA fragments, totally inappropriate for the DNA repair purpose. This MIE-DNApolβ match may serve a starting point for further move towards the paramagnetic path in current developments of anti-cancer strategies.

scholarly journals The Human SETMAR Protein Preserves Most of the Activities of the Ancestral Hsmar1 Transposase

2006 ◽  
Vol 27 (3) ◽  
pp. 1125-1132 ◽  
Author(s):  
Danxu Liu ◽  
Julien Bischerour ◽  
Azeem Siddique ◽  
Nicolas Buisine ◽  
Yves Bigot ◽  
...  
Keyword(s):  
Dna Repair ◽  
Dna Binding ◽  
Human Genome ◽  
Specific Binding ◽  
Protein A ◽  
Protein Coding ◽  
Specific Binding Sites ◽  
Human Genes ◽  
Starting Point ◽  
The Many

ABSTRACT Transposons have contributed protein coding sequences to a unexpectedly large number of human genes. Except for the V(D)J recombinase and telomerase, all remain of unknown function. Here we investigate the activity of the human SETMAR protein, a highly expressed fusion between a histone H3 methylase and a mariner family transposase. Although SETMAR has demonstrated methylase activity and a DNA repair phenotype, its mode of action and the role of the transposase domain remain obscure. As a starting point to address this problem, we have dissected the activity of the transposase domain in the context of the full-length protein and the isolated transposase domain. Complete transposition of an engineered Hsmar1 transposon by the transposase domain was detected, although the extent of the reaction was limited by a severe defect for cleavage at the 3′ ends of the element. Despite this problem, SETMAR retains robust activity for the other stages of the Hsmar1 transposition reaction, namely, site-specific DNA binding to the transposon ends, assembly of a paired-ends complex, cleavage of the 5′ end of the element in Mn2+, and integration at a TA dinucleotide target site. SETMAR is unlikely to catalyze transposition in the human genome, although the nicking activity may have a role in the DNA repair phenotype. The key activity for the mariner domain is therefore the robust DNA-binding and looping activity which has a high potential for targeting the histone methylase domain to the many thousands of specific binding sites in the human genome provided by copies of the Hsmar1 transposon.

scholarly journals Bacteria “Read” Light To Gain a Competitive Advantage

2019 ◽  
Vol 201 (10) ◽  
Author(s):  
Carolyn E. Lubner
Keyword(s):  
Dna Repair ◽  
Gene Regulation ◽  
Diurnal Cycle ◽  
Regulatory Networks ◽  
Solar Irradiation ◽  
Chemical Bonds ◽  
Repair Gene ◽  
Primary Mechanism ◽  
Dna Repair Gene ◽  
Biological Organisms

ABSTRACT Photosynthesis, the process of converting solar energy into stored chemical bonds, represents the primary mechanism by which biological organisms utilize photons. Light can also be used to activate a number of photosensory compounds and proteins designed to carry out tasks, such as DNA repair, gene regulation, and synchronization with the diurnal cycle. Given that sunlight is incident upon many environments, it is not farfetched to think that life may have evolved other as-yet-undetected mechanisms to profit from solar irradiation. In this issue, Maresca and coworkers detail their observations of light-enhanced growth of several nonphotosynthetic actinobacteria, as well as describe the potential photosensitizer responsible for this phenotype and discuss the regulatory networks involved (J. A. Maresca, J. L. Keffer, P. P. Hempel, S. W. Polson, et al., J Bacteriol 201:e00740-18, 2019, https://doi.org/10.1128/JB.00740-18). This study opens the door to many intriguing questions about the use of light as information in nonphotosynthetic biological systems.

scholarly journals An Integrative miRNA-mRNA Expression Analysis Reveals Striking Transcriptomic Similarities between Severe Equine Asthma and Specific Asthma Endotypes in Humans

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1143
Author(s):  
Matthias F. Hulliger ◽  
Alicja Pacholewska ◽  
Amandine Vargas ◽  
Jean-Pierre Lavoie ◽  
Tosso Leeb ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Regulatory Networks ◽  
Airway Remodeling ◽  
Tissue Samples ◽  
Th17 Cell Differentiation ◽  
Starting Point ◽  
Mrna Expression Analysis ◽  
Healthy Control ◽  
Equine Asthma ◽  
Transcriptomic Level

Severe equine asthma is an incurable obstructive respiratory condition affecting 10–15% of horses in temperate climates. Upon exposure to airborne antigens from hay feeding, affected horses show neutrophilic airway inflammation and bronchoconstriction, leading to increased respiratory effort. The resulting implications range from welfare concerns to economic impacts on equestrian sports and horse breeding. Immunological and pathophysiological characteristics of severe equine asthma show important parallels with allergic and severe neutrophilic human asthma. Our study aimed at investigating regulatory networks underlying the pathophysiology of the disease by profiling miRNA and mRNA expression in lung tissue samples from asthmatic horses compared with healthy controls. We sequenced small RNAs and mRNAs from lungs of seven asthmatic horses in exacerbation, five affected horses in remission, and eight healthy control horses. Our comprehensive differential expression analyses, combined with the miRNA–mRNA negative correlation approach, revealed a strong similarity on the transcriptomic level between severe equine asthma and severe neutrophilic asthma in humans, potentially through affecting Th17 cell differentiation. This study also showed that several dysregulated miRNAs and mRNAs are involved in airway remodeling. These results present a starting point for a better transcriptomic understanding of severe equine asthma and its similarities to asthma in humans.

scholarly journals Combining gene expression data and prior knowledge for inferring gene regulatory networks via Bayesian networks using structural restrictions

2019 ◽  
Vol 18 (3) ◽  
Author(s):  
Luis M. de Campos ◽  
Andrés Cano ◽  
Javier G. Castellano ◽  
Serafín Moral
Keyword(s):  
Gene Expression ◽  
Bayesian Networks ◽  
Prior Knowledge ◽  
Gene Expression Data ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cellular Systems ◽  
Expression Data ◽  
Starting Point ◽  
Gene Regulatory

Abstract Gene Regulatory Networks (GRNs) are known as the most adequate instrument to provide a clear insight and understanding of the cellular systems. One of the most successful techniques to reconstruct GRNs using gene expression data is Bayesian networks (BN) which have proven to be an ideal approach for heterogeneous data integration in the learning process. Nevertheless, the incorporation of prior knowledge has been achieved by using prior beliefs or by using networks as a starting point in the search process. In this work, the utilization of different kinds of structural restrictions within algorithms for learning BNs from gene expression data is considered. These restrictions will codify prior knowledge, in such a way that a BN should satisfy them. Therefore, one aim of this work is to make a detailed review on the use of prior knowledge and gene expression data to inferring GRNs from BNs, but the major purpose in this paper is to research whether the structural learning algorithms for BNs from expression data can achieve better outcomes exploiting this prior knowledge with the use of structural restrictions. In the experimental study, it is shown that this new way to incorporate prior knowledge leads us to achieve better reverse-engineered networks.

Identification of early gene expression changes during human Th17 cell differentiation

Blood ◽  
2012 ◽  
Vol 119 (23) ◽  
pp. e151-e160 ◽  
Author(s):  
Soile Tuomela ◽  
Verna Salo ◽  
Subhash K. Tripathi ◽  
Zhi Chen ◽  
Kirsti Laurila ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Early Gene ◽  
Th17 Cell Differentiation ◽  
Genome Wide ◽  
Starting Point ◽  
Th17 Differentiation

Abstract Th17 cells play an essential role in the pathogenesis of autoimmune and inflammatory diseases. Most of our current understanding on Th17 cell differentiation relies on studies carried out in mice, whereas the molecular mechanisms controlling human Th17 cell differentiation are less well defined. In this study, we identified gene expression changes characterizing early stages of human Th17 cell differentiation through genome-wide gene expression profiling. CD4+ cells isolated from umbilical cord blood were used to determine detailed kinetics of gene expression after initiation of Th17 differentiation with IL1β, IL6, and TGFβ. The differential expression of selected candidate genes was further validated at protein level and analyzed for specificity in initiation of Th17 compared with initiation of other Th subsets, namely Th1, Th2, and iTreg. This first genome-wide profiling of transcriptomics during the induction of human Th17 differentiation provides a starting point for defining gene regulatory networks and identifying new candidates regulating Th17 differentiation in humans.

scholarly journals Biochemical and Structural Studies of NADH-Dependent FabG Used To Increase the Bacterial Production of Fatty Acids under Anaerobic Conditions

2013 ◽  
Vol 80 (2) ◽  
pp. 497-505 ◽  
Author(s):  
Pouya Javidpour ◽  
Jose H. Pereira ◽  
Ee-Been Goh ◽  
Ryan P. McAndrew ◽  
Suzanne M. Ma ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Methyl Ketone ◽  
Fatty Acid Biosynthesis ◽  
Cell Physiology ◽  
Crystallographic Structure ◽  
Anaerobic Conditions ◽  
Content Type ◽  
Atp Production ◽  
Starting Point

ABSTRACTMajor efforts in bioenergy research have focused on producing fuels that can directly replace petroleum-derived gasoline and diesel fuel through metabolic engineering of microbial fatty acid biosynthetic pathways. Typically, growth and pathway induction are conducted under aerobic conditions, but for operational efficiency in an industrial context, anaerobic culture conditions would be preferred to obviate the need to maintain specific dissolved oxygen concentrations and to maximize the proportion of reducing equivalents directed to biofuel biosynthesis rather than ATP production. A major concern with fermentative growth conditions is elevated NADH levels, which can adversely affect cell physiology. The purpose of this study was to identify homologs ofEscherichia coliFabG, an essential reductase involved in fatty acid biosynthesis, that display a higher preference for NADH than for NADPH as a cofactor. Four potential NADH-dependent FabG variants were identified through bioinformatic analyses supported by crystallographic structure determination (1.3- to 2.0-Å resolution).In vitroassays of cofactor (NADH/NADPH) preference in the four variants showed up to ∼35-fold preference for NADH, which was observed with theCupriavidus taiwanensisFabG variant. In addition, FabG homologs were overexpressed in fatty acid- and methyl ketone-overproducingE. colihost strains under anaerobic conditions, and theC. taiwanensisvariant led to a 60% higher free fatty acid titer and 75% higher methyl ketone titer relative to the titers of the control strains. With further engineering, this work could serve as a starting point for establishing a microbial host strain for production of fatty acid-derived biofuels (e.g., methyl ketones) under anaerobic conditions.

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