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Genes, Volume 8, Issue 1 (January 2017) – 44 articles

Cover Story (view full-size image): Mec1/ATR serves as a foreman inside a yeast cell, overseeing the DNA double-stranded break (DSB) repair process. The Mec1-mediated DNA damage response results in cells undergoing aerobic fermentation instead of respiration. Mec1/ATR promotes the THO/TREX complex to translocate to the cytoplasm in response to torsional stress. Mec1, together with the chromatin remodeling factors Ino80 and Paf1, also functions to remove RNA Pol II from the template to preserve replication fork integrity when replication and transcription are in conflict. View this paper
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750 KiB  
Review
Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity
by Tony M. Mertz, Victoria Harcy and Steven A. Roberts
Genes 2017, 8(1), 46; https://doi.org/10.3390/genes8010046 - 22 Jan 2017
Cited by 26 | Viewed by 10979
Abstract
The ability of all organisms to copy their genetic information via DNA replication is a prerequisite for cell division and a biological imperative of life. In multicellular organisms, however, mutations arising from DNA replication errors in the germline and somatic cells are the [...] Read more.
The ability of all organisms to copy their genetic information via DNA replication is a prerequisite for cell division and a biological imperative of life. In multicellular organisms, however, mutations arising from DNA replication errors in the germline and somatic cells are the basis of genetic diseases and cancer, respectively. Within human tumors, replication errors additionally contribute to mutator phenotypes and tumor heterogeneity, which are major confounding factors for cancer therapeutics. Successful DNA replication involves the coordination of many large-scale, complex cellular processes. In this review, we focus on the roles that defects in enzymes that normally act at the replication fork and dysregulation of enzymes that inappropriately damage single-stranded DNA at the fork play in causing mutations that contribute to carcinogenesis. We focus on tumor data and experimental evidence that error-prone variants of replicative polymerases promote carcinogenesis and on research indicating that the primary target mutated by APOBEC (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like) cytidine deaminases is ssDNA present at the replication fork. Furthermore, we discuss evidence from model systems that indicate replication stress and other cancer-associated metabolic changes may modulate mutagenic enzymatic activities at the replication fork. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Article
Tissue Non-Specific Genes and Pathways Associated with Diabetes: An Expression Meta-Analysis
by Hao Mei, Lianna Li, Shijian Liu, Fan Jiang, Michael Griswold and Thomas Mosley
Genes 2017, 8(1), 44; https://doi.org/10.3390/genes8010044 - 21 Jan 2017
Cited by 8 | Viewed by 5261
Abstract
We performed expression studies to identify tissue non-specific genes and pathways of diabetes by meta-analysis. We searched curated datasets of the Gene Expression Omnibus (GEO) database and identified 13 and five expression studies of diabetes and insulin responses at various tissues, respectively. We [...] Read more.
We performed expression studies to identify tissue non-specific genes and pathways of diabetes by meta-analysis. We searched curated datasets of the Gene Expression Omnibus (GEO) database and identified 13 and five expression studies of diabetes and insulin responses at various tissues, respectively. We tested differential gene expression by empirical Bayes-based linear method and investigated gene set expression association by knowledge-based enrichment analysis. Meta-analysis by different methods was applied to identify tissue non-specific genes and gene sets. We also proposed pathway mapping analysis to infer functions of the identified gene sets, and correlation and independent analysis to evaluate expression association profile of genes and gene sets between studies and tissues. Our analysis showed that PGRMC1 and HADH genes were significant over diabetes studies, while IRS1 and MPST genes were significant over insulin response studies, and joint analysis showed that HADH and MPST genes were significant over all combined data sets. The pathway analysis identified six significant gene sets over all studies. The KEGG pathway mapping indicated that the significant gene sets are related to diabetes pathogenesis. The results also presented that 12.8% and 59.0% pairwise studies had significantly correlated expression association for genes and gene sets, respectively; moreover, 12.8% pairwise studies had independent expression association for genes, but no studies were observed significantly different for expression association of gene sets. Our analysis indicated that there are both tissue specific and non-specific genes and pathways associated with diabetes pathogenesis. Compared to the gene expression, pathway association tends to be tissue non-specific, and a common pathway influencing diabetes development is activated through different genes at different tissues. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Review
Burkholderia cepacia Complex Regulation of Virulence Gene Expression: A Review
by Sílvia A. Sousa, Joana R. Feliciano, Tiago Pita, Soraia I. Guerreiro and Jorge H. Leitão
Genes 2017, 8(1), 43; https://doi.org/10.3390/genes8010043 - 19 Jan 2017
Cited by 32 | Viewed by 9125
Abstract
Burkholderia cepacia complex (Bcc) bacteria emerged as opportunistic pathogens in cystic fibrosis and immunocompromised patients. Their eradication is very difficult due to the high level of intrinsic resistance to clinically relevant antibiotics. Bcc bacteria have large and complex genomes, composed of two to [...] Read more.
Burkholderia cepacia complex (Bcc) bacteria emerged as opportunistic pathogens in cystic fibrosis and immunocompromised patients. Their eradication is very difficult due to the high level of intrinsic resistance to clinically relevant antibiotics. Bcc bacteria have large and complex genomes, composed of two to four replicons, with variable numbers of insertion sequences. The complexity of Bcc genomes confers a high genomic plasticity to these bacteria, allowing their adaptation and survival to diverse habitats, including the human host. In this work, we review results from recent studies using omics approaches to elucidate in vivo adaptive strategies and virulence gene regulation expression of Bcc bacteria when infecting the human host or subject to conditions mimicking the stressful environment of the cystic fibrosis lung. Full article
(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)
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Review
Regulation of DNA Replication in Early Embryonic Cleavages
by Chames Kermi, Elena Lo Furno and Domenico Maiorano
Genes 2017, 8(1), 42; https://doi.org/10.3390/genes8010042 - 19 Jan 2017
Cited by 28 | Viewed by 8153
Abstract
Early embryonic cleavages are characterized by short and highly synchronous cell cycles made of alternating S- and M-phases with virtually absent gap phases. In this contracted cell cycle, the duration of DNA synthesis can be extraordinarily short. Depending on the organism, the whole [...] Read more.
Early embryonic cleavages are characterized by short and highly synchronous cell cycles made of alternating S- and M-phases with virtually absent gap phases. In this contracted cell cycle, the duration of DNA synthesis can be extraordinarily short. Depending on the organism, the whole genome of an embryo is replicated at a speed that is between 20 to 60 times faster than that of a somatic cell. Because transcription in the early embryo is repressed, DNA synthesis relies on a large stockpile of maternally supplied proteins stored in the egg representing most, if not all, cellular genes. In addition, in early embryonic cell cycles, both replication and DNA damage checkpoints are inefficient. In this article, we will review current knowledge on how DNA synthesis is regulated in early embryos and discuss possible consequences of replicating chromosomes with little or no quality control. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Review
RNA Editing, ADAR1, and the Innate Immune Response
by Qingde Wang, Xiaoni Li, Ruofan Qi and Timothy Billiar
Genes 2017, 8(1), 41; https://doi.org/10.3390/genes8010041 - 18 Jan 2017
Cited by 33 | Viewed by 11118
Abstract
RNA editing, particularly A-to-I RNA editing, has been shown to play an essential role in mammalian embryonic development and tissue homeostasis, and is implicated in the pathogenesis of many diseases including skin pigmentation disorder, autoimmune and inflammatory tissue injury, neuron degeneration, and various [...] Read more.
RNA editing, particularly A-to-I RNA editing, has been shown to play an essential role in mammalian embryonic development and tissue homeostasis, and is implicated in the pathogenesis of many diseases including skin pigmentation disorder, autoimmune and inflammatory tissue injury, neuron degeneration, and various malignancies. A-to-I RNA editing is carried out by a small group of enzymes, the adenosine deaminase acting on RNAs (ADARs). Only three members of this protein family, ADAR1–3, exist in mammalian cells. ADAR3 is a catalytically null enzyme and the most significant function of ADAR2 was found to be in editing on the neuron receptor GluR-B mRNA. ADAR1, however, has been shown to play more significant roles in biological and pathological conditions. Although there remains much that is not known about how ADAR1 regulates cellular function, recent findings point to regulation of the innate immune response as an important function of ADAR1. Without appropriate RNA editing by ADAR1, endogenous RNA transcripts stimulate cytosolic RNA sensing receptors and therefore activate the IFN-inducing signaling pathways. Overactivation of innate immune pathways can lead to tissue injury and dysfunction. However, obvious gaps in our knowledge persist as to how ADAR1 regulates innate immune responses through RNA editing. Here, we review critical findings from ADAR1 mechanistic studies focusing on its regulatory function in innate immune responses and identify some of the important unanswered questions in the field. Full article
(This article belongs to the Special Issue RNA Editing)
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Article
Genome Analysis of a Novel Broad Host Range Proteobacteria Phage Isolated from a Bioreactor Treating Industrial Wastewater
by Marina De Leeuw, Maayan Baron, Asher Brenner and Ariel Kushmaro
Genes 2017, 8(1), 40; https://doi.org/10.3390/genes8010040 - 18 Jan 2017
Cited by 10 | Viewed by 6394
Abstract
Bacteriophages are viruses that infect bacteria, and consequently they have a major impact on the development of a microbial population. In this study, the genome of a novel broad host range bacteriophage, Aquamicrobium phage P14, isolated from a wastewater treatment plant, was analyzed. [...] Read more.
Bacteriophages are viruses that infect bacteria, and consequently they have a major impact on the development of a microbial population. In this study, the genome of a novel broad host range bacteriophage, Aquamicrobium phage P14, isolated from a wastewater treatment plant, was analyzed. The Aquamicrobium phage P14 was found to infect members of different Proteobacteria classes (Alphaproteobacteria and Betaproteobacteria). This phage contains a 40,551 bp long genome and 60% of its genes had blastx hits. Furthermore, the bacteriophage was found to share more than 50% of its genes with several podoviruses and has the same gene order as other polyvalent bacteriophages. The results obtained in this study led to the conclusion that indeed general features of the genome of the Aquamicrobium phage P14 are shared with other broad host range bacteriophages, however further analysis of the genome is needed in order to identify the specific mechanisms which enable the bacteriophage to infect both Alphaproteobacteria and Betaproteobacteria. Full article
(This article belongs to the Section Microbial Genetics and Genomics)
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Review
The Complex Relationship between Virulence and Antibiotic Resistance
by Meredith Schroeder, Benjamin D. Brooks and Amanda E. Brooks
Genes 2017, 8(1), 39; https://doi.org/10.3390/genes8010039 - 18 Jan 2017
Cited by 187 | Viewed by 19287
Abstract
Antibiotic resistance, prompted by the overuse of antimicrobial agents, may arise from a variety of mechanisms, particularly horizontal gene transfer of virulence and antibiotic resistance genes, which is often facilitated by biofilm formation. The importance of phenotypic changes seen in a biofilm, which [...] Read more.
Antibiotic resistance, prompted by the overuse of antimicrobial agents, may arise from a variety of mechanisms, particularly horizontal gene transfer of virulence and antibiotic resistance genes, which is often facilitated by biofilm formation. The importance of phenotypic changes seen in a biofilm, which lead to genotypic alterations, cannot be overstated. Irrespective of if the biofilm is single microbe or polymicrobial, bacteria, protected within a biofilm from the external environment, communicate through signal transduction pathways (e.g., quorum sensing or two-component systems), leading to global changes in gene expression, enhancing virulence, and expediting the acquisition of antibiotic resistance. Thus, one must examine a genetic change in virulence and resistance not only in the context of the biofilm but also as inextricably linked pathologies. Observationally, it is clear that increased virulence and the advent of antibiotic resistance often arise almost simultaneously; however, their genetic connection has been relatively ignored. Although the complexities of genetic regulation in a multispecies community may obscure a causative relationship, uncovering key genetic interactions between virulence and resistance in biofilm bacteria is essential to identifying new druggable targets, ultimately providing a drug discovery and development pathway to improve treatment options for chronic and recurring infection. Full article
(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)
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Article
Sulfolobus acidocaldarius UDG Can Remove dU from the RNA Backbone: Insight into the Specific Recognition of Uracil Linked with Deoxyribose
by Gang-Shun Yi, Wei-Wei Wang, Wei-Guo Cao, Feng-Ping Wang and Xi-Peng Liu
Genes 2017, 8(1), 38; https://doi.org/10.3390/genes8010038 - 18 Jan 2017
Cited by 4 | Viewed by 4593
Abstract
Sulfolobus acidocaldarius encodes family 4 and 5 uracil-DNA glycosylase (UDG). Two recombinant S. acidocaldarius UDGs (SacUDG) were prepared and biochemically characterized using oligonucleotides carrying a deaminated base. Both SacUDGs can remove deoxyuracil (dU) base from both double-stranded DNA and single-stranded DNA. Interestingly, they [...] Read more.
Sulfolobus acidocaldarius encodes family 4 and 5 uracil-DNA glycosylase (UDG). Two recombinant S. acidocaldarius UDGs (SacUDG) were prepared and biochemically characterized using oligonucleotides carrying a deaminated base. Both SacUDGs can remove deoxyuracil (dU) base from both double-stranded DNA and single-stranded DNA. Interestingly, they can remove U linked with deoxyribose from single-stranded RNA backbone, suggesting that the riboses on the backbone have less effect on the recognition of dU and hydrolysis of the C-N glycosidic bond. However, the removal of rU from DNA backbone is inefficient, suggesting strong steric hindrance comes from the 2′ hydroxyl of ribose linked to uracil. Both SacUDGs cannot remove 2,2′-anhydro uridine, hypoxanthine, and 7-deazaxanthine from single-stranded DNA and single-stranded DNA. Compared with the family 2 MUG, other family UDGs have an extra N-terminal structure consisting of about 50 residues. Removal of the 46 N-terminal residues of family 5 SacUDG resulted in only a 40% decrease in activity, indicating that the [4Fe-4S] cluster and truncated secondary structure are not the key elements in hydrolyzing the glycosidic bond. Combining our biochemical and structural results with those of other groups, we discussed the UDGs’ catalytic mechanism and the possible repair reactions of deaminated bases in prokaryotes. Full article
(This article belongs to the Special Issue Replication and Transcription Associated DNA Repair)
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Review
Centromere Stability: The Replication Connection
by Susan L. Forsburg and Kuo-Fang Shen
Genes 2017, 8(1), 37; https://doi.org/10.3390/genes8010037 - 18 Jan 2017
Cited by 8 | Viewed by 5301
Abstract
The fission yeast centromere, which is similar to metazoan centromeres, contains highly repetitive pericentromere sequences that are assembled into heterochromatin. This is required for the recruitment of cohesin and proper chromosome segregation. Surprisingly, the pericentromere replicates early in the S phase. Loss of [...] Read more.
The fission yeast centromere, which is similar to metazoan centromeres, contains highly repetitive pericentromere sequences that are assembled into heterochromatin. This is required for the recruitment of cohesin and proper chromosome segregation. Surprisingly, the pericentromere replicates early in the S phase. Loss of heterochromatin causes this domain to become very sensitive to replication fork defects, leading to gross chromosome rearrangements. This review examines the interplay between components of DNA replication, heterochromatin assembly, and cohesin dynamics that ensures maintenance of genome stability and proper chromosome segregation. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Review
Familial Lung Cancer: A Brief History from the Earliest Work to the Most Recent Studies
by Anthony M. Musolf, Claire L. Simpson, Mariza De Andrade, Diptasri Mandal, Colette Gaba, Ping Yang, Yafang Li, Ming You, Elena Y. Kupert, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos and Joan E. Bailey-Wilson
Genes 2017, 8(1), 36; https://doi.org/10.3390/genes8010036 - 17 Jan 2017
Cited by 17 | Viewed by 6361
Abstract
Lung cancer is the deadliest cancer in the United States, killing roughly one of four cancer patients in 2016. While it is well-established that lung cancer is caused primarily by environmental effects (particularly tobacco smoking), there is evidence for genetic susceptibility. Lung cancer [...] Read more.
Lung cancer is the deadliest cancer in the United States, killing roughly one of four cancer patients in 2016. While it is well-established that lung cancer is caused primarily by environmental effects (particularly tobacco smoking), there is evidence for genetic susceptibility. Lung cancer has been shown to aggregate in families, and segregation analyses have hypothesized a major susceptibility locus for the disease. Genetic association studies have provided strong evidence for common risk variants of small-to-moderate effect. Rare and highly penetrant alleles have been identified by linkage studies, including on 6q23–25. Though not common, some germline mutations have also been identified via sequencing studies. Ongoing genomics studies aim to identify additional high penetrance germline susceptibility alleles for this deadly disease. Full article
(This article belongs to the Special Issue Cancer Genetics)
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Article
Integrative miRNA-Gene Expression Analysis Enables Refinement of Associated Biology and Prediction of Response to Cetuximab in Head and Neck Squamous Cell Cancer
by Loris De Cecco, Marco Giannoccaro, Edoardo Marchesi, Paolo Bossi, Federica Favales, Laura D. Locati, Lisa Licitra, Silvana Pilotti and Silvana Canevari
Genes 2017, 8(1), 35; https://doi.org/10.3390/genes8010035 - 14 Jan 2017
Cited by 25 | Viewed by 6097
Abstract
This paper documents the process by which we, through gene and miRNA expression profiling of the same samples of head and neck squamous cell carcinomas (HNSCC) and an integrative miRNA-mRNA expression analysis, were able to identify candidate biomarkers of progression-free survival (PFS) in [...] Read more.
This paper documents the process by which we, through gene and miRNA expression profiling of the same samples of head and neck squamous cell carcinomas (HNSCC) and an integrative miRNA-mRNA expression analysis, were able to identify candidate biomarkers of progression-free survival (PFS) in patients treated with cetuximab-based approaches. Through sparse partial least square–discriminant analysis (sPLS-DA) and supervised analysis, 36 miRNAs were identified in two components that clearly separated long- and short-PFS patients. Gene set enrichment analysis identified a significant correlation between the miRNA first-component and EGFR signaling, keratinocyte differentiation, and p53. Another significant correlation was identified between the second component and RAS, NOTCH, immune/inflammatory response, epithelial–mesenchymal transition (EMT), and angiogenesis pathways. Regularized canonical correlation analysis of sPLS-DA miRNA and gene data combined with the MAGIA2 web-tool highlighted 16 miRNAs and 84 genes that were interconnected in a total of 245 interactions. After feature selection by a smoothed t-statistic support vector machine, we identified three miRNAs and five genes in the miRNA-gene network whose expression result was the most relevant in predicting PFS (Area Under the Curve, AUC = 0.992). Overall, using a well-defined clinical setting and up-to-date bioinformatics tools, we are able to give the proof of principle that an integrative miRNA-mRNA expression could greatly contribute to the refinement of the biology behind a predictive model. Full article
(This article belongs to the Special Issue microRNAs and Other Non-Coding RNAs in Human Diseases)
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Article
Applying Human ADAR1p110 and ADAR1p150 for Site-Directed RNA Editing—G/C Substitution Stabilizes GuideRNAs against Editing
by Madeleine Heep, Pia Mach, Philipp Reautschnig, Jacqueline Wettengel and Thorsten Stafforst
Genes 2017, 8(1), 34; https://doi.org/10.3390/genes8010034 - 14 Jan 2017
Cited by 23 | Viewed by 6620
Abstract
Site-directed RNA editing is an approach to reprogram genetic information at the RNA level. We recently introduced a novel guideRNA that allows for the recruitment of human ADAR2 to manipulate genetic information. Here, we show that the current guideRNA design is already able [...] Read more.
Site-directed RNA editing is an approach to reprogram genetic information at the RNA level. We recently introduced a novel guideRNA that allows for the recruitment of human ADAR2 to manipulate genetic information. Here, we show that the current guideRNA design is already able to recruit another human deaminase, ADAR1, in both isoforms, p110 and p150. However, further optimization seems necessary as the current design is less efficient for ADAR1 isoforms. Furthermore, we describe hotspots at which the guideRNA itself is edited and show a way to circumvent this auto-editing without losing editing efficiency at the target. Both findings are important for the advancement of site-directed RNA editing as a tool in basic biology or as a platform for therapeutic editing. Full article
(This article belongs to the Special Issue RNA Editing)
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Review
Replication Fork Protection Factors Controlling R-Loop Bypass and Suppression
by Emily Yun-Chia Chang and Peter C. Stirling
Genes 2017, 8(1), 33; https://doi.org/10.3390/genes8010033 - 14 Jan 2017
Cited by 27 | Viewed by 11242
Abstract
Replication–transcription conflicts have been a well-studied source of genome instability for many years and have frequently been linked to defects in RNA processing. However, recent characterization of replication fork-associated proteins has revealed that defects in fork protection can directly or indirectly stabilize R-loop [...] Read more.
Replication–transcription conflicts have been a well-studied source of genome instability for many years and have frequently been linked to defects in RNA processing. However, recent characterization of replication fork-associated proteins has revealed that defects in fork protection can directly or indirectly stabilize R-loop structures in the genome and promote transcription–replication conflicts that lead to genome instability. Defects in essential DNA replication-associated activities like topoisomerase, or the minichromosome maintenance (MCM) helicase complex, as well as fork-associated protection factors like the Fanconi anemia pathway, both appear to mitigate transcription–replication conflicts. Here, we will highlight recent advances that support the concept that normal and robust replisome function itself is a key component of mitigating R-loop coupled genome instability. Full article
(This article belongs to the Special Issue R-loop Biology in Eukaryotes)
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Article
Characterization of the Transcriptome and Gene Expression of Brain Tissue in Sevenband Grouper (Hyporthodus septemfasciatus) in Response to NNV Infection
by Jong-Oh Kim, Jae-Ok Kim, Wi-Sik Kim and Myung-Joo Oh
Genes 2017, 8(1), 31; https://doi.org/10.3390/genes8010031 - 13 Jan 2017
Cited by 22 | Viewed by 4760
Abstract
Grouper is one of the favorite sea food resources in Southeast Asia. However, the outbreaks of the viral nervous necrosis (VNN) disease due to nervous necrosis virus (NNV) infection have caused mass mortality of grouper larvae. Many aqua-farms have suffered substantial financial loss [...] Read more.
Grouper is one of the favorite sea food resources in Southeast Asia. However, the outbreaks of the viral nervous necrosis (VNN) disease due to nervous necrosis virus (NNV) infection have caused mass mortality of grouper larvae. Many aqua-farms have suffered substantial financial loss due to the occurrence of VNN. To better understand the infection mechanism of NNV, we performed the transcriptome analysis of sevenband grouper brain tissue, the main target of NNV infection. After artificial NNV challenge, transcriptome of brain tissues of sevenband grouper was subjected to next generation sequencing (NGS) using an Illumina Hi-seq 2500 system. Both mRNAs from pooled samples of mock and NNV-infected sevenband grouper brains were sequenced. Clean reads of mock and NNV-infected samples were de novo assembled and obtained 104,348 unigenes. In addition, 628 differentially expressed genes (DEGs) in response to NNV infection were identified. This result could provide critical information not only for the identification of genes involved in NNV infection, but for the understanding of the response of sevenband groupers to NNV infection. Full article
(This article belongs to the Section Microbial Genetics and Genomics)
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Editorial
Acknowledgement to Reviewers of Genes in 2016
by Genes Editorial Office
Genes 2017, 8(1), 30; https://doi.org/10.3390/genes8010030 - 13 Jan 2017
Cited by 5 | Viewed by 3070
Abstract
The editors of Genes would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016. We greatly appreciate the contribution of expert reviewers, which is crucial to the journal’s editorial process. We aim to recognize reviewer contributions through [...] Read more.
The editors of Genes would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016. We greatly appreciate the contribution of expert reviewers, which is crucial to the journal’s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make. If you are interested in becoming a reviewer for Genes, see the link at the bottom of the webpage https://www.mdpi.com/reviewers. Full article
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Erratum
Erratum: Pan Y. et al. Cucumber Metallothionein-Like 2 (CsMTL2) Exhibits Metal-Binding Properties. Genes 2016, 7, 106
by Genes Editorial Office
Genes 2017, 8(1), 29; https://doi.org/10.3390/genes8010029 - 12 Jan 2017
Cited by 14 | Viewed by 2367
(This article belongs to the Section Molecular Genetics and Genomics)
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Article
Transgenic Tobacco Expressing the TAT-Helicokinin I-CpTI Fusion Protein Show Increased Resistance and Toxicity to Helicoverpa armigera (Lepidoptera: Noctuidae)
by Zhou Zhou, Yongli Li, Chunyan Yuan, Yongan Zhang and Liangjian Qu
Genes 2017, 8(1), 28; https://doi.org/10.3390/genes8010028 - 12 Jan 2017
Cited by 3 | Viewed by 4159
Abstract
Insect kinins were shown to have diuretic activity, inhibit weight gain, and have antifeedant activity in insects. In order to study the potential of the TAT-fusion approach to deliver diuretic peptides per os to pest insects, the HezK I peptide from Helicoverpa zea [...] Read more.
Insect kinins were shown to have diuretic activity, inhibit weight gain, and have antifeedant activity in insects. In order to study the potential of the TAT-fusion approach to deliver diuretic peptides per os to pest insects, the HezK I peptide from Helicoverpa zea, as a representative of the kinin family, was selected. The fusion gene TAT-HezK I was designed and was used to transform tobacco plants. As a means to further improve the stability of TAT-HezK I, a fusion protein incorporating HezK I, transactivator of transcription (TAT), and the cowpea trypsin inhibitor (CpTI) was also designed. Finally, the toxicity of the different tobacco transgenic strains toward Helicoverpa armigera was compared. The results demonstrated that TAT-HezK I had high toxicity against insects via transgenic expression of the peptide in planta and intake through larval feeding. The toxicity of the fusion TAT-HezK I and CpTI was higher than the CpTI single gene in transgenic tobacco, and the fusion TAT-HezK I and CpTI further enhanced the stability and bioavailability of agents in oral administration. Our research helps in targeting new genes for improving herbivore tolerance in transgenic plant breeding. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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Article
Identification of the Ovine Keratin-Associated Protein 22-1 (KAP22-1) Gene and Its Effect on Wool Traits
by Shaobin Li, Huitong Zhou, Hua Gong, Fangfang Zhao, Jiqing Wang, Xiu Liu, Yuzhu Luo and Jon G. H. Hickford
Genes 2017, 8(1), 27; https://doi.org/10.3390/genes8010027 - 11 Jan 2017
Cited by 40 | Viewed by 4690
Abstract
Keratin-associated proteins (KAPs) are structural components of wool and hair fibers. To date, eight high glycine/tyrosine KAP (HGT-KAP) families have been identified in humans, but only three have been identified in sheep. In this study, the putative ovine homolog of the human KAP22-1 [...] Read more.
Keratin-associated proteins (KAPs) are structural components of wool and hair fibers. To date, eight high glycine/tyrosine KAP (HGT-KAP) families have been identified in humans, but only three have been identified in sheep. In this study, the putative ovine homolog of the human KAP22-1 gene (KRTAP22-1) was amplified using primers designed based on a human KRTAP22-1 sequence. Polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) was used to screen for variation in KRTAP22-1 in 390 Merino × Southdown-cross lambs and 75 New Zealand (NZ) Romney sheep. Three PCR-SSCP banding patterns were detected and DNA sequencing revealed that the banding patterns represented three different nucleotide sequences (A–C). Two single nucleotide polymorphisms (SNPs) were identified in these sequences. Variant B was most common with a frequency of 81.3% in NZ Romney sheep, while in the Merino × Southdown-cross lambs, A was more common with a frequency of 51.8%. The presence of B was found to be associated with increased wool yield and decreased mean fiber curvature (MFC). Sheep of genotype BB or AB had a higher wool yield than those of genotype AA. These results suggest that ovine KRTAP22-1 variation may be useful when developing breeding programs based on increasing wool yield, or decreasing wool curvature. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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Review
Origin DNA Melting—An Essential Process with Divergent Mechanisms
by Matthew P. Martinez, John M. Jones, Irina Bruck and Daniel L. Kaplan
Genes 2017, 8(1), 26; https://doi.org/10.3390/genes8010026 - 11 Jan 2017
Cited by 7 | Viewed by 5804
Abstract
Origin DNA melting is an essential process in the various domains of life. The replication fork helicase unwinds DNA ahead of the replication fork, providing single-stranded DNA templates for the replicative polymerases. The replication fork helicase is a ring shaped-assembly that unwinds DNA [...] Read more.
Origin DNA melting is an essential process in the various domains of life. The replication fork helicase unwinds DNA ahead of the replication fork, providing single-stranded DNA templates for the replicative polymerases. The replication fork helicase is a ring shaped-assembly that unwinds DNA by a steric exclusion mechanism in most DNA replication systems. While one strand of DNA passes through the central channel of the helicase ring, the second DNA strand is excluded from the central channel. Thus, the origin, or initiation site for DNA replication, must melt during the initiation of DNA replication to allow for the helicase to surround a single-DNA strand. While this process is largely understood for bacteria and eukaryotic viruses, less is known about how origin DNA is melted at eukaryotic cellular origins. This review describes the current state of knowledge of how genomic DNA is melted at a replication origin in bacteria and eukaryotes. We propose that although the process of origin melting is essential for the various domains of life, the mechanism for origin melting may be quite different among the different DNA replication initiation systems. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Article
AAC as a Potential Target Gene to Control Verticillium dahliae
by Xiaofeng Su, Latifur Rehman, Huiming Guo, Xiaokang Li, Rui Zhang and Hongmei Cheng
Genes 2017, 8(1), 25; https://doi.org/10.3390/genes8010025 - 10 Jan 2017
Cited by 10 | Viewed by 5282
Abstract
Verticillium dahliae invades the roots of host plants and causes vascular wilt, which seriously diminishes the yield of cotton and other important crops. The protein AAC (ADP, ATP carrier) is responsible for transferring ATP from the mitochondria into the cytoplasm. When V. dahliae [...] Read more.
Verticillium dahliae invades the roots of host plants and causes vascular wilt, which seriously diminishes the yield of cotton and other important crops. The protein AAC (ADP, ATP carrier) is responsible for transferring ATP from the mitochondria into the cytoplasm. When V. dahliae protoplasts were transformed with short interfering RNAs (siRNAs) targeting the VdAAC gene, fungal growth and sporulation were significantly inhibited. To further confirm a role for VdAAC in fungal development, we generated knockout mutants (ΔVdACC). Compared with wild-type V. dahliae (Vd wt), ΔVdAAC was impaired in germination and virulence; these impairments were rescued in the complementary strains (ΔVdAAC-C). Moreover, when an RNAi construct of VdAAC under the control of the 35S promoter was used to transform Nicotiana benthamiana, the expression of VdAAC was downregulated in the transgenic seedlings, and they had elevated resistance against V. dahliae. The results of this study suggest that VdAAC contributes to fungal development, virulence and is a promising candidate gene to control V. dahliae. In addition, RNAi is a highly efficient way to silence fungal genes and provides a novel strategy to improve disease resistance in plants. Full article
(This article belongs to the Special Issue RNA Interference 2016)
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Review
Translesion Synthesis: Insights into the Selection and Switching of DNA Polymerases
by Linlin Zhao and M. Todd Washington
Genes 2017, 8(1), 24; https://doi.org/10.3390/genes8010024 - 10 Jan 2017
Cited by 54 | Viewed by 8421
Abstract
DNA replication is constantly challenged by DNA lesions, noncanonical DNA structures and difficult-to-replicate DNA sequences. Two major strategies to rescue a stalled replication fork and to ensure continuous DNA synthesis are: (1) template switching and recombination-dependent DNA synthesis; and (2) translesion synthesis (TLS) [...] Read more.
DNA replication is constantly challenged by DNA lesions, noncanonical DNA structures and difficult-to-replicate DNA sequences. Two major strategies to rescue a stalled replication fork and to ensure continuous DNA synthesis are: (1) template switching and recombination-dependent DNA synthesis; and (2) translesion synthesis (TLS) using specialized DNA polymerases to perform nucleotide incorporation opposite DNA lesions. The former pathway is mainly error-free, and the latter is error-prone and a major source of mutagenesis. An accepted model of translesion synthesis involves DNA polymerase switching steps between a replicative DNA polymerase and one or more TLS DNA polymerases. The mechanisms that govern the selection and exchange of specialized DNA polymerases for a given DNA lesion are not well understood. In this review, recent studies concerning the mechanisms of selection and switching of DNA polymerases in eukaryotic systems are summarized. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Review
Control of Initiation of DNA Replication in Bacillus subtilis and Escherichia coli
by Katie H. Jameson and Anthony J. Wilkinson
Genes 2017, 8(1), 22; https://doi.org/10.3390/genes8010022 - 10 Jan 2017
Cited by 42 | Viewed by 14149
Abstract
Initiation of DNA Replication is tightly regulated in all cells since imbalances in chromosomal copy number are deleterious and often lethal. In bacteria such as Bacillus subtilis and Escherichia coli, at the point of cytokinesis, there must be two complete copies of [...] Read more.
Initiation of DNA Replication is tightly regulated in all cells since imbalances in chromosomal copy number are deleterious and often lethal. In bacteria such as Bacillus subtilis and Escherichia coli, at the point of cytokinesis, there must be two complete copies of the chromosome to partition into the daughter cells following division at mid-cell during vegetative growth. Under conditions of rapid growth, when the time taken to replicate the chromosome exceeds the doubling time of the cells, there will be multiple initiations per cell cycle and daughter cells will inherit chromosomes that are already undergoing replication. In contrast, cells entering the sporulation pathway in B. subtilis can do so only during a short interval in the cell cycle when there are two, and only two, chromosomes per cell, one destined for the spore and one for the mother cell. Here, we briefly describe the overall process of DNA replication in bacteria before reviewing initiation of DNA replication in detail. The review covers DnaA-directed assembly of the replisome at oriC and the multitude of mechanisms of regulation of initiation, with a focus on the similarities and differences between E. coli and B. subtilis. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Review
Targeting MicroRNAs in Cancer Gene Therapy
by Weidan Ji, Bin Sun and Changqing Su
Genes 2017, 8(1), 21; https://doi.org/10.3390/genes8010021 - 09 Jan 2017
Cited by 148 | Viewed by 9955
Abstract
MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged [...] Read more.
MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer. Full article
(This article belongs to the Special Issue Gene Therapy)
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Article
Contribution of the RgfD Quorum Sensing Peptide to rgf Regulation and Host Cell Association in Group B Streptococcus
by Robert E. Parker, David Knupp, Rim Al Safadi, Agnѐs Rosenau and Shannon D. Manning
Genes 2017, 8(1), 23; https://doi.org/10.3390/genes8010023 - 06 Jan 2017
Cited by 10 | Viewed by 7410
Abstract
Streptococcus agalactiae (group B Streptococcus; GBS) is a common inhabitant of the genitourinary and/or gastrointestinal tract in up to 40% of healthy adults; however, this opportunistic pathogen is able to breach restrictive host barriers to cause disease and persist in harsh and [...] Read more.
Streptococcus agalactiae (group B Streptococcus; GBS) is a common inhabitant of the genitourinary and/or gastrointestinal tract in up to 40% of healthy adults; however, this opportunistic pathogen is able to breach restrictive host barriers to cause disease and persist in harsh and changing conditions. This study sought to identify a role for quorum sensing, a form of cell to cell communication, in the regulation of the fibrinogen-binding (rgfBDAC) two-component system and the ability to associate with decidualized endometrial cells in vitro. To do this, we created a deletion in rgfD, which encodes the putative autoinducing peptide, in a GBS strain belonging to multilocus sequence type (ST)-17 and made comparisons to the wild type. Sequence variation in the rgf operon was detected in 40 clinical strains and a non-synonymous single nucleotide polymorphism was detected in rgfD in all of the ST-17 genomes that resulted in a truncation. Using qPCR, expression of rgf operon genes was significantly decreased in the ST-17 ΔrgfD mutant during exponential growth with the biggest difference (3.3-fold) occurring at higher cell densities. Association with decidualized endometrial cells was decreased 1.3-fold in the mutant relative to the wild type and rgfC expression was reduced 22-fold in ΔrgfD following exposure to the endometrial cells. Collectively, these data suggest that this putative quorum sensing molecule is important for attachment to human tissues and demonstrate a role for RgfD in GBS pathogenesis through regulation of rgfC. Full article
(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)
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Review
PrimPol—Prime Time to Reprime
by Thomas A. Guilliam and Aidan J. Doherty
Genes 2017, 8(1), 20; https://doi.org/10.3390/genes8010020 - 06 Jan 2017
Cited by 47 | Viewed by 12814
Abstract
The complex molecular machines responsible for genome replication encounter many obstacles during their progression along DNA. Tolerance of these obstructions is critical for efficient and timely genome duplication. In recent years, primase-polymerase (PrimPol) has emerged as a new player involved in maintaining eukaryotic [...] Read more.
The complex molecular machines responsible for genome replication encounter many obstacles during their progression along DNA. Tolerance of these obstructions is critical for efficient and timely genome duplication. In recent years, primase-polymerase (PrimPol) has emerged as a new player involved in maintaining eukaryotic replication fork progression. This versatile replicative enzyme, a member of the archaeo-eukaryotic primase (AEP) superfamily, has the capacity to perform a range of template-dependent and independent synthesis activities. Here, we discuss the emerging roles of PrimPol as a leading strand repriming enzyme and describe the mechanisms responsible for recruiting and regulating the enzyme during this process. This review provides an overview and update of the current PrimPol literature, as well as highlighting unanswered questions and potential future avenues of investigation. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Review
Maintenance of Genome Integrity: How Mammalian Cells Orchestrate Genome Duplication by Coordinating Replicative and Specialized DNA Polymerases
by Ryan Barnes and Kristin Eckert
Genes 2017, 8(1), 19; https://doi.org/10.3390/genes8010019 - 06 Jan 2017
Cited by 22 | Viewed by 7367
Abstract
Precise duplication of the human genome is challenging due to both its size and sequence complexity. DNA polymerase errors made during replication, repair or recombination are central to creating mutations that drive cancer and aging. Here, we address the regulation of human DNA [...] Read more.
Precise duplication of the human genome is challenging due to both its size and sequence complexity. DNA polymerase errors made during replication, repair or recombination are central to creating mutations that drive cancer and aging. Here, we address the regulation of human DNA polymerases, specifically how human cells orchestrate DNA polymerases in the face of stress to complete replication and maintain genome stability. DNA polymerases of the B-family are uniquely adept at accurate genome replication, but there are numerous situations in which one or more additional DNA polymerases are required to complete genome replication. Polymerases of the Y-family have been extensively studied in the bypass of DNA lesions; however, recent research has revealed that these polymerases play important roles in normal human physiology. Replication stress is widely cited as contributing to genome instability, and is caused by conditions leading to slowed or stalled DNA replication. Common Fragile Sites epitomize “difficult to replicate” genome regions that are particularly vulnerable to replication stress, and are associated with DNA breakage and structural variation. In this review, we summarize the roles of both the replicative and Y-family polymerases in human cells, and focus on how these activities are regulated during normal and perturbed genome replication. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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3147 KiB  
Article
Error-Free Bypass of 7,8-dihydro-8-oxo-2′-deoxyguanosine by DNA Polymerase of Pseudomonas aeruginosa Phage PaP1
by Shiling Gu, Qizhen Xue, Qin Liu, Mei Xiong, Wanneng Wang and Huidong Zhang
Genes 2017, 8(1), 18; https://doi.org/10.3390/genes8010018 - 06 Jan 2017
Cited by 15 | Viewed by 4611
Abstract
As one of the most common forms of oxidative DNA damage, 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxoG) generally leads to G:C to T:A mutagenesis. To study DNA replication encountering 8-oxoG by the sole DNA polymerase (Gp90) of Pseudomonas aeruginosa phage PaP1, we performed steady-state and pre-steady-state kinetic [...] Read more.
As one of the most common forms of oxidative DNA damage, 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxoG) generally leads to G:C to T:A mutagenesis. To study DNA replication encountering 8-oxoG by the sole DNA polymerase (Gp90) of Pseudomonas aeruginosa phage PaP1, we performed steady-state and pre-steady-state kinetic analyses of nucleotide incorporation opposite 8-oxoG by Gp90 D234A that lacks exonuclease activities on ssDNA and dsDNA substrates. Gp90 D234A could bypass 8-oxoG in an error-free manner, preferentially incorporate dCTP opposite 8-oxoG, and yield similar misincorporation frequency to unmodified G. Gp90 D234A could extend beyond C:8-oxoG or A:8-oxoG base pairs with the same efficiency. dCTP incorporation opposite G and dCTP or dATP incorporation opposite 8-oxoG showed fast burst phases. The burst of incorporation efficiency (kpol/Kd,dNTP) is decreased as dCTP:G > dCTP:8-oxoG > dATP:8-oxoG. The presence of 8-oxoG in DNA does not affect its binding to Gp90 D234A in a binary complex but it does affect it in a ternary complex with dNTP and Mg2+, and dATP misincorporation opposite 8-oxoG further weakens the binding of Gp90 D234A to DNA. This study reveals Gp90 D234A can bypass 8-oxoG in an error-free manner, providing further understanding in DNA replication encountering oxidation lesion for P.aeruginosa phage PaP1. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Article
Type 2 Diabetes Susceptibility in the Greek-Cypriot Population: Replication of Associations with TCF7L2, FTO, HHEX, SLC30A8 and IGF2BP2 Polymorphisms
by Christina Votsi, Costas Toufexis, Kyriaki Michailidou, Athos Antoniades, Nicos Skordis, Minas Karaolis, Constantinos S. Pattichis and Kyproula Christodoulou
Genes 2017, 8(1), 16; https://doi.org/10.3390/genes8010016 - 06 Jan 2017
Cited by 22 | Viewed by 5515
Abstract
Type 2 diabetes (T2D) has been the subject of numerous genetic studies in recent years which revealed associations of the disease with a large number of susceptibility loci. We hereby initiate the evaluation of T2D susceptibility loci in the Greek-Cypriot population by performing [...] Read more.
Type 2 diabetes (T2D) has been the subject of numerous genetic studies in recent years which revealed associations of the disease with a large number of susceptibility loci. We hereby initiate the evaluation of T2D susceptibility loci in the Greek-Cypriot population by performing a replication case-control study. One thousand and eighteen individuals (528 T2D patients, 490 controls) were genotyped at 21 T2D susceptibility loci, using the allelic discrimination method. Statistically significant associations of T2D with five of the tested single nucleotide polymorphisms (SNPs) (TCF7L2 rs7901695, FTO rs8050136, HHEX rs5015480, SLC30A8 rs13266634 and IGF2BP2 rs4402960) were observed in this study population. Furthermore, 14 of the tested SNPs had odds ratios (ORs) in the same direction as the previously published studies, suggesting that these variants can potentially be used in the Greek-Cypriot population for predictive testing of T2D. In conclusion, our findings expand the genetic assessment of T2D susceptibility loci and reconfirm five of the worldwide established loci in a distinct, relatively small, newly investigated population. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Review
Effects of Replication and Transcription on DNA Structure-Related Genetic Instability
by Guliang Wang and Karen M. Vasquez
Genes 2017, 8(1), 17; https://doi.org/10.3390/genes8010017 - 05 Jan 2017
Cited by 54 | Viewed by 10995
Abstract
Many repetitive sequences in the human genome can adopt conformations that differ from the canonical B-DNA double helix (i.e., non-B DNA), and can impact important biological processes such as DNA replication, transcription, recombination, telomere maintenance, viral integration, transposome activation, DNA damage and repair. [...] Read more.
Many repetitive sequences in the human genome can adopt conformations that differ from the canonical B-DNA double helix (i.e., non-B DNA), and can impact important biological processes such as DNA replication, transcription, recombination, telomere maintenance, viral integration, transposome activation, DNA damage and repair. Thus, non-B DNA-forming sequences have been implicated in genetic instability and disease development. In this article, we discuss the interactions of non-B DNA with the replication and/or transcription machinery, particularly in disease states (e.g., tumors) that can lead to an abnormal cellular environment, and how such interactions may alter DNA replication and transcription, leading to potential conflicts at non-B DNA regions, and eventually result in genetic stability and human disease. Full article
(This article belongs to the Special Issue Replication and Transcription Associated DNA Repair)
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Review
Quorum Sensing Regulation of Competence and Bacteriocins in Streptococcus pneumoniae and mutans
by Erin Shanker and Michael J. Federle
Genes 2017, 8(1), 15; https://doi.org/10.3390/genes8010015 - 05 Jan 2017
Cited by 121 | Viewed by 15063
Abstract
The human pathogens Streptococcus pneumoniae and Streptococcus mutans have both evolved complex quorum sensing (QS) systems that regulate the production of bacteriocins and the entry into the competent state, a requirement for natural transformation. Natural transformation provides bacteria with a mechanism to repair [...] Read more.
The human pathogens Streptococcus pneumoniae and Streptococcus mutans have both evolved complex quorum sensing (QS) systems that regulate the production of bacteriocins and the entry into the competent state, a requirement for natural transformation. Natural transformation provides bacteria with a mechanism to repair damaged genes or as a source of new advantageous traits. In S. pneumoniae, the competence pathway is controlled by the two-component signal transduction pathway ComCDE, which directly regulates SigX, the alternative sigma factor required for the initiation into competence. Over the past two decades, effectors of cellular killing (i.e., fratricides) have been recognized as important targets of the pneumococcal competence QS pathway. Recently, direct interactions between the ComCDE and the paralogous BlpRH pathway, regulating bacteriocin production, were identified, further strengthening the interconnections between these two QS systems. Interestingly, a similar theme is being revealed in S. mutans, the primary etiological agent of dental caries. This review compares the relationship between the bacteriocin and the competence QS pathways in both S. pneumoniae and S. mutans, and hopes to provide clues to regulatory pathways across the genus Streptococcus as a potential tool to efficiently investigate putative competence pathways in nontransformable streptococci. Full article
(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)
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