Rad53- and Chk1-Dependent DNA Damage Response Pathways Cooperatively Promote Fungal Pathogenesis and Modulate Antifungal Drug Susceptibility
Ontology highlight
ABSTRACT:
ORGANISM(S): Cryptococcus neoformans var. grubii
PROVIDER: GSE117227 | GEO | 2018/12/04
REPOSITORIES: GEO
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2024-09-02 | BIOMD0000000475 | BioModels
Project description:One of the most likely risks astronauts on long duration space missions face is exposure to ionizing radiation associated with highly energetic and charged heavy (HZE) particles. Since access to medical expertise on such a mission is limited at best, early diagnosis and mitigation of such exposure is critical. In order to accurately determine the dosage within 1 hour post-exposure, dose-dependent “biomarkers” are needed. Therefore, we performed a dose-course transcriptional analysis for radiation exposure at 0, 0.3, 1.5, and 3.0 Gy with corresponding time point at 1 hour (hr) post-exposure using Affymetrix® GeneChip® Human Gene 1.0 ST v1 Array chips. The analysis of our data suggests a set of sensitive genetic biomarkers specific to each radiation level as well as generic radiation response biomarkers. Upregulated biomarkers can then be used within lab-on-a-chip (LOC) systems to detect exposure to ionizing radiation.
2016-01-01 | GSE64375 | GEO
Project description:Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. For BALB/c mice, a total of 357, 480, and 335 lncRNAs and 550, 911, and 389 coding RNAs were identified at 2, 4, and 8 weeks post-irradiation, respectively, while for SPRET/EiJ, a total of 327 lncRNAs and 424 mRNAs were identified at 4 weeks post-irradiation.
2014-12-01 | GSE62662 | GEO
Project description:Living organisms are constantly exposed to DNA damage stress caused by endogenous and exogenous events. Eukaryotic cells have evolutionarily conserved DNA damage checkpoint surveillance systems. We previously reported that a unique transcription factor, Bdr1, whose expression is strongly induced by the protein kinase Rad53 governs DNA damage responses by controlling the expression of DNA repair genes in the basidiomycetous fungus Cryptococcus neoformans However, the regulatory mechanism of the Rad53-dependent DNA damage signal cascade and its function in pathogenicity remain unclear. Here, we demonstrate that Rad53 is required for DNA damage response and is phosphorylated by two phosphatidylinositol 3-kinase (PI3K)-like kinases, Tel1 and Mec1, in response to DNA damage stress. Transcriptome analysis revealed that Rad53 regulates the expression of several DNA repair genes in response to gamma radiation. We found that expression of CHK1, another effector kinase involved in the DNA damage response, is regulated by Rad53 and that CHK1 deletion rendered cells highly susceptible to DNA damage stress. Nevertheless, BDR1 expression is regulated by Rad53, but not Chk1, indicating that DNA damage signal cascades mediated by Rad53 and Chk1 exhibit redundant and distinct functions. We found that perturbation of both RAD53 and CHK1 attenuated the virulence of C. neoformans, perhaps by promoting phagosome maturation within macrophage, reducing melanin production, and increasing susceptibility to oxidative stresses. Furthermore, deletion of both RAD53 and CHK1 increased susceptibility to certain antifungal drugs such as amphotericin B. This report provides insight into the regulatory mechanism of fungal DNA damage repair systems and their functional relationship with fungal virulence and antifungal drug susceptibility.IMPORTANCE Genome instability is detrimental for living things because it induces genetic disorder diseases and transfers incorrect genome information to descendants. Therefore, living organisms have evolutionarily conserved signaling networks to sense and repair DNA damage. However, how the DNA damage response pathway is regulated for maintaining the genome integrity of fungal pathogens and how this contributes to their pathogenicity remain elusive. In this study, we investigated the DNA damage response pathway in the basidiomycete pathogen Cryptococcus neoformans, which causes life-threatening meningoencephalitis in immunocompromised individuals, with an average of 223,100 infections leading to 181,100 deaths reported annually. Here, we found that perturbation of Rad53- and Chk1-dependent DNA damage response pathways attenuated the virulence of C. neoformans and increased its susceptibility to certain antifungal drugs, such as amphotericin B and flucytosine. Therefore, our work paves the way to understanding the important role of human fungal DNA damage networks in pathogenesis and antifungal drug susceptibility.
| S-EPMC6315099 | biostudies-literature
Project description:One of the most likely risks astronauts on long duration space missions face is exposure to ionizing radiation associated with highly energetic and charged heavy (HZE) particles. Since access to medical expertise on such a mission is limited at best, early diagnosis and mitigation of such exposure is critical. In order to accurately determine the dosage within 1 hour post-exposure, dose-dependent âbiomarkersâ are needed. Therefore, we performed a dose-course transcriptional analysis for radiation exposure at 0, 0.3, 1.5, and 3.0 Gy with corresponding time point at 1 hour (hr) post-exposure using Affymetrix® GeneChip® Human Gene 1.0 ST v1 Array chips. The analysis of our data suggests a set of sensitive genetic biomarkers specific to each radiation level as well as generic radiation response biomarkers. Upregulated biomarkers can then be used within lab-on-a-chip (LOC) systems to detect exposure to ionizing radiation. A total of sixteen human samples representing radiation exposure at levels 0 Gy, 0.3 Gy, 1.5 Gy and 3.0 Gy at time point 1 hour (hr) post-exposure were constructed. Blood samples were extracted from four human volunteers, and were irradiated. Leukocytes were extracted, and gene expression was measured. Samples for all four volunteers were measured at 1 hr for all four dose levels, resulting in four replicates at each dose level. Thus, a total of 4 samples at each of the four radiation levels were sampled, yielding the total of 16 samples.
2016-07-03 | E-GEOD-64375 | biostudies-arrayexpress
Project description:Increased use of nuclear reactors and radioactive materials for energy production and proliferation of nuclear weaponry increases risk of radiation exposure or nuclear accidents. Development of radiation countermeasures for the diagnosis, prognosis, and radiation treatment are trailing behind, and knowledge of the deleterious radiation effects on health and responses to exposure at the molecular, cellular, and systems biology level are still not fully understood. In this work, skin biopsies collected at h2, d4, d7, d21, and d28 from mice exposed to 1, 3, 6, 20Gy of whole-body x-ray ionizing radiation were used in a transcriptomic approach to evaluate the potential of radiation-induced transcriptional alterations in diagnosis and prognosis of a radiation event. Mice exposed to 20Gy were euthanized under the humane endpoint of an IACUC approved study protocol at d7 while mice that received 1, 3, 6Gy survived the full 28 days time course. Sammon plot analysis showed a clear separation of samples based on survival and timepoints within lethal (20Gy) and in the sublethal (1, 3, 6Gy) IR doses. Differences in the numbers, regulation mode, and fold change of significantly differentially transcribed genes (SDTGs, p < 0.05 and FC > 2) were identified between lethal and sublethal doses. Down and upregulation dominated transcriptomes during the first post-exposure week, respectively. Numbers of SDTGs and percentages of upregulated SDTGs revealed stationary transcription and low upregulation percentages after lethal dose in contrary to transcription responses that were dynamic and largely upregulated after exposure to sublethal doses. Longitudinal variations in numbers of up/downregulated SDTGs suggested delayed and extended responses with increasing IR doses in the sublethal range with lethal-like responses in late time points suggesting more than a single-phase response. This was supported further by the distributions of common and unique genes across the TPs within each dose. Several genes with potential use as markers for radiation exposure and dosimetric applications were identified. Pathways enrichment analysis showed strong modulations of immune responses, fibrosis development, detoxification responses, hematological responses, skin reactions, neurological system disruptions, maintenance of gastric mucosa, and cell survival, migration, and proliferation pathways. The majority of the identified pathways were predicted activated after sublethal and inactivated after lethal exposures, particularly during the first post-exposure week.
2022-03-15 | GSE185149 | GEO
Project description:Purpose: DNA methylation has a global impact on gene expression Methods: Gene expression profiles of D. radiodurans R1 wild type and ΔM.DraR1 strains were generated by deep sequencing using Illumina HiSeqTM2500. Results: RNA-seq was used for differential expression gene analysis between wild-type and ΔM.DraR1 strains. A total of 1158 genes (766 upregulated genes and 392 downregulated genes) were differentially expressed in ΔM.DraR1 strain. GO enrichment analysis revealed that upregulated unigenes were significantly enriched in twelve subcategories. The majority of unigenes in the biological process category were associated with macromolecule metabolic processes. Interestingly, a number of unigenes were also associated with DNA recombination. Within the molecular function category, most unigenes were assigned to nucleic acid, DNA binding and hydrolase, and nucleoside triphosphatase activity. The KEGG enrichment analytical scatter diagram showed that the major pathways affected in the deletion strain belonged to ABC transport, two-component systems, DNA replication, homologous recombination, and protein export pathways. The majority of DNA damage response genes, such as ddrA, ddrB, ddrO, ddrG, ddrJ, ddrK, ddrD and pprA, were significantly upregulated. Several genes involved in DNA recombinational repair pathway including recA, recO, rexD, and ruvB were also significantly upregulated. Putative competence genes, including those encoding prepilin peptidase, CRP and CinA, were upregulated in the mutant strain. This gene expression pattern of the ΔM.DraR1 strain resembled that of D. radiodurans during recovery after exposure to acute radiation, indicating that the absence of N4-cytosine DNA methylation may result in intracellular stress. Conclusion: Absence of N4-cytosine DNA Methylation in D. radiodurans Leads to Expression Changes of Proteins Involved in DNA Damage Response
2019-07-27 | GSE134934 | GEO
Project description:Purpose: Members of the broadly distributed Rid/YER057c/UK114 protein family have imine/enamine deaminase activity, notably on a 2-aminoacrylate (2AA). Strains of Salmonella enterica, and other organisms lacking RidA, have diverse growth phenotypes, attributed to the accumulation of 2AA. The goal of this study was to use transcriptional differences between S. enterica wild-type and ridA strains to explore the breadth of the cellular consequences that resulted from accumulation of 2AA. Methods: S. enterica LT2 mRNA profiles of wild-type (WT) and ridA mutant cells were generated by Next Generation Sequencing, in biological quadruplicate, using Illumina Nextseq (150 cycles) Mid Output Flowcell in the paired end mode with a read length of 75bp. The sequence reads that passed quality filters were analyzed by DEseq to call for statistically significant (FDR < 0.05) differential gene expression. qRT–PCR experiemnts were performed using SYBR Green assays to corroborate the differential expression for 9 of the genes identified as differentially expressed. Results: Pair-wise comparison of gene expression identified 413 genes with statistically significant changes (186 higher expression, and 227 lower expression) in transcript abundance between ridA mutant and wild-type strains (FDR < 0.05). Of these loci,when genes with no known function (STMxxxx and yxxX locus tags--120 genes) and genes showing less than a two-fold difference in expression were excluded, 84 genes remained which showed differential expression between strains. RNA-seq data had a linear relationship with qRT–PCR for four genes (napF, metH, dadX, and fliI) belonging to the 84 gene dataset, one gene (thiF) with an FDR < 0.05, but failing the two-fold cutoff threshold and one gene (sdaC) that did not meet the statistical cutoff (FDR > 005). Pearson's correlation coefficient (R2) for the relationship between RNAseq and qRT-PCR data was measured at 0.96. Analysis of the differentially expressed genes uncovered several areas of metabolism and physiology which may be affected by RidA elimination, and subsequent 2-aminoacrylate accumulation. Conclusions: Our study represents the first detailed analysis on the transcriptional effect RidA elimination has in S. enterica LT2, using biologic replicates, and generated by RNA-seq technology. Our results uncovered a motility effect associated with the accumulation of 2-aminoacrylate in a ridA mutant as well as identified additional areas of metabolism impacted by the metabolic stress associated with 2AA accumulation. These data also emphasized the value of integrating global approaches with biochemical genetic approaches to understand the complex system of microbial metabolism.
2017-08-28 | GSE103146 | GEO
Project description:Red light radiation has been proven to provide clinical benefits to human health. Our investigation was conducted to characterize tissue morphology of mouse breast post 660 nm-laser radiation with low power and long-term exposure.
2022-07-04 | GSE207183 | GEO
Project description:This study tracks the proteome during recovery from 10 kGy acute ionizing radiation (IR) in Deinococcus radiodurans R1 (WT). After 1 hour of recovery post-IR exposure, we observed 37 proteins significantly differentially expressed, including several within the Radiation and Dessication Response (RDR) pathway. Additionally, we also explored the regulatory network of a sRNA named PprS (previously Dsr2) in Deinococcus radiodurans by comparing the proteome of a sRNA knockdown strain (PprSKD, which demonstrates a ~2-fold decrease in PprS expression) to WT D. radiodurans during unirradiated conditions at late-exponential phase. Comparison between these two strains demonstrated decreased levels of one of PprS's targets, PprM, in the PprSKD strain which validated the activation mechanism we propose for PprS on pprM.
2021-06-25 | PXD026633 | Pride