Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans

2021 ◽  
Vol 70 (3) ◽  
Author(s):  
Bala S. C. Koritala ◽  
Kenneth I. Porter ◽  
Osama A. Arshad ◽  
Rajendra P. Gajula ◽  
Hugh D. Mitchell ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Night Shift ◽  
Dna Repair Genes ◽  
Shift Schedule ◽  
Repair Genes

Patients with Systemic Sclerosis Present Increased DNA Damage Differentially Associated with DNA Repair Gene Polymorphisms

2014 ◽  
Vol 41 (3) ◽  
pp. 458-465 ◽  
Author(s):  
Gustavo Martelli Palomino ◽  
Carmen L. Bassi ◽  
Isabela J. Wastowski ◽  
Danilo J. Xavier ◽  
Yara M. Lucisano-Valim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Systemic Sclerosis ◽  
Blood Cells ◽  
Gene Polymorphisms ◽  
Peripheral Blood Cells ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Repair Genes

Objective.Patients with systemic sclerosis (SSc) exhibit increased toxicity when exposed to genotoxic agents. In our study, we evaluated DNA damage and polymorphic sites in 2 DNA repair genes (XRCC1Arg399Gln andXRCC4Ile401Thr) in patients with SSc.Methods.A total of 177 patients were studied for DNA repair gene polymorphisms. Fifty-six of them were also evaluated for DNA damage in peripheral blood cells using the comet assay.Results.Compared to controls, the patients as a whole or stratified into major clinical variants (limited or diffuse skin involvement), irrespective of the underlying treatment schedule, exhibited increased DNA damage.XRCC1(rs: 25487) andXRCC4(rs: 28360135) allele and genotype frequencies observed in patients with SSc were not significantly different from those observed in controls; however, theXRCC1Arg399Gln allele was associated with increased DNA damage only in healthy controls and theXRCC4Ile401Thr allele was associated with increased DNA damage in both patients and controls. Further, theXRCC1Arg399Gln allele was associated with the presence of antinuclear antibody and anticentromere antibody. No association was observed between these DNA repair gene polymorphic sites and clinical features of patients with SSc.Conclusion.These results corroborate the presence of genomic instability in SSc peripheral blood cells, as evaluated by increased DNA damage, and show that polymorphic sites of theXRCC1andXRCC4DNA repair genes may differentially influence DNA damage and the development of autoantibodies.

Endometrial DNA damage response is modulated in endometriosis

2020 ◽  
Author(s):  
Kashmira Bane ◽  
Junita Desouza ◽  
Diksha Shetty ◽  
Prakash Choudhary ◽  
Shalaka Kadam ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Small Sample ◽  
Nuclear Antigen ◽  
Dna Repair Genes ◽  
Eutopic Endometrium ◽  
Damage Response ◽  
Repair Genes

Abstract STUDY QUESTION Is the DNA damage response (DDR) dysregulated in the eutopic endometrium of women with endometriosis? SUMMARY ANSWER Endometrial expression of genes involved in DDR is modulated in women with endometriosis, compared to those without the disease. WHAT IS KNOWN ALREADY Ectopic endometriotic lesions are reported to harbour somatic mutations, thereby hinting at dysregulation of DDR and DNA repair pathways. However, it remains inconclusive whether the eutopic endometrium also manifests dysregulated DDR in endometriosis. STUDY DESIGN, SIZE, DURATION For this case–control study conducted between 2015 and 2019, eutopic endometrial (E) samples (EE- from women with endometriosis, CE- from women without endometriosis) were collected in either mid-proliferative (EE-MP, n = 23; CE-MP, n = 17) or mid-secretory (EE-MS, n = 17; CE-MS, n = 9) phases of the menstrual cycle. This study compares: (i) DNA damage marker localization, (ii) expression of DDR genes and (iii) expression of DNA repair genes in eutopic endometrial samples from women with and without endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS The study included (i) 40 women (aged 31.9 ± 0.81 years) with endometriosis and (ii) 26 control women (aged 31.4 ± 1.02 years) without endometriosis. Eutopic endometrial samples from the two groups were divided into different parts for histological analysis, immunohistochemistry, RNA extraction, protein extraction and comet assays. Eighty-four genes of relevance in the DNA damage signalling pathway were evaluated for their expression in eutopic endometrial samples, using RT2 Profiler PCR arrays. Validations of the expression of two GADD (Growth Arrest DNA Damage Inducible) proteins - GADD45A and GADD45G were carried out by immunoblotting. DNA damage was assessed by immunohistochemical localization of γ-H2AFX (a phosphorylated variant of histone H2AX) and 8-OHdG (8-hydroxy-2′-deoxyguanosine). RNA sequencing data from mid-proliferative (EE-MP, n = 4; CE-MP, n = 3) and mid-secretory phase (EE-MS and CE-MS, n = 4 each) endometrial samples were scanned to compare the expression status of all the genes implicated in human DNA repair. PCNA (Proliferating Cell Nuclear Antigen) expression was determined to assess endometrial proliferation. Residual DNA damage in primary endometrial cells was checked by comet assays. Public datasets were also scanned for the expression of DDR and DNA repair genes as our RNASeq data were limited by small sample size. All the comparisons were made between phase-matched endometrial samples from women with and without endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE Endometrial expression of DDR genes and intensity of immunolocalized γ-H2AFX were significantly (P < 0.05) higher in EE, compared to CE samples. DDR proteins, especially those belonging to the GADD family, were found to be differentially abundant in EE, as compared to CE. These patterns were evident in both mid-proliferative and mid-secretory phases. Intriguingly, higher DDR was associated with increased cell proliferation in EE-MP, compared to CE-MP. Furthermore, among the differentially expressed transcripts (DETs) encoded by DNA repair genes, the majority showed up-regulation in EE-MP, compared to CE-MP. Interestingly, CE-MP and EE-MP had a comparable percentage (P > 0.05) of cells with residual DNA damage. However, unlike the mid-proliferative phase data, many DETs encoded by DNA repair genes were down-regulated in EE-MS, compared to CE-MS. An analysis of the phase-matched control and endometriosis samples included in the GSE51981 dataset available in the Gene Expression Omnibus database also revealed significant (P < 0.05) alterations in the expression of DDR and DNA repair genes in EE, compared to CE. LARGE-SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION The study was conducted on a limited number of endometrial samples. Also, the study does not reveal the causes underlying dysregulated DDR in the eutopic endometrium of women with endometriosis. WIDER IMPLICATIONS OF THE FINDINGS Alterations in the expression of DDR and DNA repair genes indirectly suggest that eutopic endometrium, as compared to its healthy counterpart, encounters DNA damage-inducing stimuli, either of higher strength or for longer duration in endometriosis. It will be worthwhile to identify the nature of such stimuli and also explore the role of higher genomic insults and dysregulated DDR/DNA repair in the origin and/or progression of endometriosis. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the Department of Biotechnology and Indian Council of Medical Research, Government of India. No conflict of interest is declared.

scholarly journals Yeast Rpn4 Links the Proteasome and DNA Repair via RAD52 Regulation

2020 ◽  
Vol 21 (21) ◽  
pp. 8097
Author(s):  
Daria S. Spasskaya ◽  
Nonna I. Nadolinskaia ◽  
Vera V. Tutyaeva ◽  
Yuriy P. Lysov ◽  
Vadim L. Karpov ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Proteasome Inhibition ◽  
26S Proteasome ◽  
Dependent Manner ◽  
Dna Repair Genes ◽  
Damage Resistance ◽  
Dna Damaging Agents ◽  
Mutant Strains ◽  
Repair Genes

Environmental and intracellular factors often damage DNA, but multiple DNA repair pathways maintain genome integrity. In yeast, the 26S proteasome and its transcriptional regulator and substrate Rpn4 are involved in DNA damage resistance. Paradoxically, while proteasome dysfunction may induce hyper-resistance to DNA-damaging agents, Rpn4 malfunction sensitizes yeasts to these agents. Previously, we proposed that proteasome inhibition causes Rpn4 stabilization followed by the upregulation of Rpn4-dependent DNA repair genes and pathways. Here, we aimed to elucidate the key Rpn4 targets responsible for DNA damage hyper-resistance in proteasome mutants. We impaired the Rpn4-mediated regulation of candidate genes using the CRISPR/Cas9 system and tested the sensitivity of mutant strains to 4-NQO, MMS and zeocin. We found that the separate or simultaneous deregulation of 19S or 20S proteasome subcomplexes induced MAG1, DDI1, RAD23 and RAD52 in an Rpn4-dependent manner. Deregulation of RAD23, DDI1 and RAD52 sensitized yeast to DNA damage. Genetic, epigenetic or dihydrocoumarin-mediated RAD52 repression restored the sensitivity of the proteasome mutants to DNA damage. Our results suggest that the Rpn4-mediated overexpression of DNA repair genes, especially RAD52, defines the DNA damage hyper-resistant phenotype of proteasome mutants. The developed yeast model is useful for characterizing drugs that reverse the DNA damage hyper-resistance phenotypes of cancers.

Genetic polymorphisms and possible gene–gene interactions in metabolic and DNA repair genes: Effects on DNA damage

2006 ◽  
Vol 593 (1-2) ◽  
pp. 22-31 ◽  
Author(s):  
Alessio Naccarati ◽  
Pavel Soucek ◽  
Rudolf Stetina ◽  
Vincent Haufroid ◽  
Rajiv Kumar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genetic Polymorphisms ◽  
Gene Interactions ◽  
Dna Repair Genes ◽  
Repair Genes

scholarly journals The Clinical Significance of DNA Damage Repair Signatures in Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Ergang Guo ◽  
Cheng Wu ◽  
Jun Ming ◽  
Wei Zhang ◽  
Linli Zhang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Dna Repair Genes ◽  
Cell Renal Cell Carcinoma ◽  
Damage Repair ◽  
Repair Genes

DNA damage repair plays an important role in cancer’s initiation and progression, and in therapeutic resistance. The prognostic potential of damage repair indicators was studied in the case of clear cell renal cell carcinoma (ccRCC). Gene expression profiles of the disease were downloaded from cancer genome databases and gene ontology was applied to the DNA repair-related genes. Twenty-six differentially expressed DNA repair genes were identified, and regression analysis was used to identify those with prognostic potential and to construct a risk model. The model accurately predicted patient outcomes and distinguished among patients with different expression levels of immune evasion genes. The data indicate that DNA repair genes can be valuable for predicting the progression of clear cell renal cell carcinoma and the clinical benefits of immunotherapy.

scholarly journals Genoprotective effects of Chaga mushroom (Inonotus obliquus) polysaccharides in UVB-exposed embryonic zebrafish (Danio rerio) through coordinated expression of DNA repair genes

2020 ◽  
Author(s):  
Jehane Ibrahim Eid ◽  
Swabhiman Mohanty ◽  
Biswadeep Das
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Model Organisms ◽  
Zebrafish Embryos ◽  
Dna Repair Genes ◽  
Genotoxic Effects ◽  
Inonotus Obliquus ◽  
Acridine Orange Staining ◽  
Uvb Exposure ◽  
Repair Genes

AbstractBackgroundChaga mushroom (Inonotus obliquus) is one of the most promising antioxidants with incredible health-promoting effects. Chaga polysaccharides (IOP) have been reported to enhance immune response and alleviate oxidative stress during development. However, the effects of IOP on the genotoxicity in model organisms are yet to be clarified.MethodsZebrafish embryos (12 hours post fertilization, hpf) were exposed to transient UVB (12 J/m2/s, 310 nm) for 10 secs using a UV hybridisation chamber, followed by IOP treatment (2.5 mg/mL) at 24 hpf for up to 7 days post fertilization (dpf). The genotoxic effects were assessed using acridine orange staining, alkaline comet assay, and qRT-PCR for screening DNA repair genes.ResultsWe found significant reduction in DNA damage and amelioration of the deformed structures in the IOP-treated zebrafish exposed to UVB (p < 0.05) at 5 dpf and thereafter. In addition, the relative mRNA expressions of XRCC-5, XRCC-6, RAD51, P53, and GADD45 were significantly upregulated in the IOP-treated UVB-exposed zebrafish. Pathway analysis demonstrated coordinated regulation of DNA repair genes, suggesting collective response during UVB exposure.ConclusionsOverall, IOP treatment ameliorated the genotoxic effects in UVB-exposed zebrafish embryos, which eventually assisted in normal development. The study suggested the efficacy of Chaga mushroom polysaccharides in mitigating UV-induced DNA damage.

scholarly journals 0025 Circadian Dysregulation of DNA Repair and Increased Endogenous and Exogenous Sensitivity to DNA Damage Precipitate Elevated Cancer Risk Associated with Night Shift Work

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A10-A10
Author(s):  
H Van Dongen ◽  
B Koritala ◽  
J E McDermott ◽  
K I Porter ◽  
O A Arshad ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Risk ◽  
Shift Work ◽  
Clock Genes ◽  
Night Shift ◽  
Night Shift Work ◽  
Shift Schedule ◽  
Γh2ax Foci ◽  
Damage Response

Abstract Introduction The elevated cancer risk associated with night shift work is poorly understood. To investigate whether circadian disruption may play a role, we assessed the circadian transcriptome and its association with hallmark cancer pathways, as well as sensitivity to endogenous and exogenous sources of DNA damage, after in-laboratory simulated shift work. Methods N=14 healthy humans (aged 22-34y; 10m, 4f) were exposed to a simulated night shift schedule (daytime sleep: 10:00-18:00) or a simulated day shift schedule (nighttime sleep: 22:00-06:00) for 3 days (n=7 in each condition). After the simulated shift schedule, subjects underwent a 24h constant routine protocol, during which blood was collected every 3h. Lymphocytes were extracted from the blood samples and subjected to transcriptome analysis using a NanoString multiplex assay. We evaluated 726 mRNA cancer hallmark targets (NanoString PanCancer Pathway Panel) and 17 circadian clock genes, with 18 arrhythmic internal controls. Gene expression was analyzed for circadian rhythmicity using mixed-effects cosinor analysis. Further, lymphocytes were investigated for DNA damage using an alkaline comet assay and immunofluorescence assessment of DNA damage response biomarkers BRCA1 and γH2AX. Lymphocytes collected at 07:30 and 19:30 were also exposed to ionizing radiation (2.5Gy) and DNA damage response assessments were repeated. Results Simulated night shift caused widespread disruption of circadian rhythmicity, as measured under constant routine, for core clock genes and the transcriptome of cancer hallmark pathways. The DNA repair pathway showed significant enrichment of rhythmic genes (p&lt;0.05) after the simulated day shift schedule only. Following simulated night shift, lymphocytes showed induction of endogenous DNA damage, with extended tail in the comet assay (p&lt;0.001), and higher percentage of lymphocytes with BRCA1 and γH2AX foci (p&lt;0.01). Lymphocytes collected at 19:30 showed enhanced impact of ionizing radiation as indicated by increased prevalence of cells with BRCA1 and γH2AX foci (p&lt;0.05). Conclusion Circadian dysregulation of DNA repair mechanisms and increased sensitivity to DNA damage following night shift work may increase genomic instability and precipitate elevated cancer risk in night shift workers. Support NIH grants ES022640 and CA227381, CDMRP award W81XWH-18-1-0100, and Pacific Northwest National Laboratory BRAVE investment under DOE contract DE-AC05-76RL01830.

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