Impact of arsenic on nucleotide excision repair: XPC function, protein level, and gene expression

2009 ◽  
Vol 53 (5) ◽  
pp. 572-582 ◽  
Author(s):  
Maike Nollen ◽  
Franziska Ebert ◽  
Jill Moser ◽  
Leon H. F. Mullenders ◽  
Andrea Hartwig ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nucleotide Excision Repair ◽  
Protein Level ◽  
Excision Repair ◽  
Nucleotide Excision ◽  
Impact Of Arsenic

31 Effect of vitrification on global gene expression dynamics of bovine elongating embryos

2020 ◽  
Vol 32 (2) ◽  
pp. 141
Author(s):  
Z. Jiang ◽  
E. Gutierrez ◽  
H. Ming ◽  
B. Foster ◽  
L. Gatenby ◽  
...  
Keyword(s):  
Gene Expression ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Cell Junction ◽  
Rna Seq ◽  
Protein Ubiquitination ◽  
Stage Of Development ◽  
Nucleotide Excision

The ability to cryopreserve gametes and embryos has been a valuable tool for reproductive management in all mammalian species, especially livestock. Embryo vitrification involves exposure to high concentrations of cryoprotectants and osmotic stress during cooling and warming. These factors have to affect gene expression. The elongating embryo is a stage of embryo development that can be recovered noninvasively in the cow on day (D) 14 and represents a critical stage of development when many embryos die. In this study, we aimed to evaluate the effect of vitrification on the transcriptome dynamics of D14 embryos by RNA sequencing (RNA-seq). Invitro blastocyst-stage embryos were vitrified by exposure to dimethyl sulfoxide and ethylene glycol solution, followed by placing on Cryo Loks and plunging in liquid nitrogen. After warming, embryos were loaded into straws and transferred into eight synchronized recipients, four cows received nonvitrified embryos and four cows received vitrified embryos (20 embryos per cow). Embryo flushing yielded 12 nonvitrified and 9 vitrified viable D14 embryos. Whole embryos (six nonvitrified and two vitrified embryos) or isolated trophectoderm (TE; four nonvitrified and seven vitrified) were processed for RNA-seq. The Smart-sEqn 2 protocol was followed to prepare RNA-seq libraries. Sequencing reads were prefiltered and aligned to the bovine genome, and gene expression values were calculated as fragments per kilobase of transcript per million mapped reads. Genes were deemed differentially expressed between treatments if they showed a false discovery rate P-value<0.05 and fold-change >2. Ingenuity pathway analysis was used to reveal gene ontology and pathways. Expression of 927 genes was changed in D14 embryos as a result of vitrification, with 782 and 145 genes upregulated and downregulated, respectively. In TE, vitrification resulted in 4096 and 280 upregulated or downregulated genes, respectively. Several pathways were upregulated by vitrification in both whole embryos and TE, including epithelial adherens junctions, sirtuin signalling, germ cell-Sertoli cell junction, ATM signalling, nucleotide excision repair, and protein ubiquitination pathways. Downregulated pathways included EIF2 signalling, oxidative phosphorylation, mitochondrial dysfunction, regulation of eIF4 and p70S6K signalling, mammalian target of rapamycin signalling, sirtuin singling, and nucleotide excision repair pathways. In addition, we found 671 and 61 genes upregulated and downregulated in both vitrified whole embryos and TE. Mitochondrial dysfunction and oxidative phosphorylation signalling were upregulated, whereas epithelial adherens junction and sirtuin signalling were downregulated, suggesting mitochondrial function and energy production were impaired in TE after vitrification. Our analysis identified specific pathways and implicated specific genes affected by cryopreservation and potentially affecting embryo developmental competence.

scholarly journals C. elegans TFIIH subunit GTF-2H5/TTDA is a non-essential transcription factor indispensable for DNA repair

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Karen L. Thijssen ◽  
Melanie van der Woude ◽  
Carlota Davó-Martínez ◽  
Dick H. W. Dekkers ◽  
Mariangela Sabatella ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Nucleotide Excision Repair ◽  
Developmental Disorder ◽  
Excision Repair ◽  
C Elegans ◽  
Nucleotide Excision ◽  
Or Gene ◽  
Essential Transcription Factor

AbstractThe 10-subunit TFIIH complex is vital to transcription and nucleotide excision repair. Hereditary mutations in its smallest subunit, TTDA/GTF2H5, cause a photosensitive form of the rare developmental disorder trichothiodystrophy. Some trichothiodystrophy features are thought to be caused by subtle transcription or gene expression defects. TTDA/GTF2H5 knockout mice are not viable, making it difficult to investigate TTDA/GTF2H5 in vivo function. Here we show that deficiency of C. elegans TTDA ortholog GTF-2H5 is, however, compatible with life, in contrast to depletion of other TFIIH subunits. GTF-2H5 promotes TFIIH stability in multiple tissues and is indispensable for nucleotide excision repair, in which it facilitates recruitment of TFIIH to DNA damage. Strikingly, when transcription is challenged, gtf-2H5 embryos die due to the intrinsic TFIIH fragility in absence of GTF-2H5. These results support the idea that TTDA/GTF2H5 mutations cause transcription impairment underlying trichothiodystrophy and establish C. elegans as model for studying pathogenesis of this disease.

scholarly journals A Gene Expression Signature to Predict Nucleotide Excision Repair Defects and Novel Therapeutic Approaches

2021 ◽  
Vol 22 (9) ◽  
pp. 5008
Author(s):  
Rongbin Wei ◽  
Hui Dai ◽  
Jing Zhang ◽  
David J. H. Shih ◽  
Yulong Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nucleotide Excision Repair ◽  
Cell Lines ◽  
Excision Repair ◽  
Gene Expression Signature ◽  
Gene Signature ◽  
Expression Signature ◽  
Nucleotide Excision ◽  
Functionally Impaired ◽  
Synthetically Lethal

Nucleotide excision repair (NER) resolves DNA adducts, such as those caused by ultraviolet light. Deficient NER (dNER) results in a higher mutation rate that can predispose to cancer development and premature ageing phenotypes. Here, we used isogenic dNER model cell lines to establish a gene expression signature that can accurately predict functional NER capacity in both cell lines and patient samples. Critically, none of the identified NER deficient cell lines harbored mutations in any NER genes, suggesting that the prevalence of NER defects may currently be underestimated. Identification of compounds that induce the dNER gene expression signature led to the discovery that NER can be functionally impaired by GSK3 inhibition, leading to synergy when combined with cisplatin treatment. Furthermore, we predicted and validated multiple novel drugs that are synthetically lethal with NER defects using the dNER gene signature as a drug discovery platform. Taken together, our work provides a dynamic predictor of NER function that may be applied for therapeutic stratification as well as development of novel biological insights in human tumors.

scholarly journals Nucleotide Excision Repair (NER) Is Frequently Impaired and Affects Outcome in Multiple Myeloma (MM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2055-2055
Author(s):  
Raphael Szalat ◽  
Matija Dreze ◽  
Mehmet Kemal Samur ◽  
Anne S. Calkins ◽  
Giovanni Parmigiani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Dna Repair ◽  
Genomic Instability ◽  
Nucleotide Excision Repair ◽  
Cell Lines ◽  
Excision Repair ◽  
Sequencing Data ◽  
Nucleotide Excision

Abstract Introduction Multiple Myeloma (MM) is a heterogeneous disease characterized by genomic instability and eventual poor outcome. Aberrations in DNA repair-related pathways have been considered to explain the instability. Nucleotide excision repair (NER) is an important pathway involved in the removal of bulky adducts and DNA crosslinks induced by various genotoxins. Little is known about the relationship between NER in MM biology and patient outcomes. Here we assess the role of NER in MM. Methods We evaluated NER efficiency in a panel of MM cell lines (n=18), with a functional assay based on the purified DNA-Damage Binding protein 2 (DDB2) complex (DDB2 proteo-probe, Dreze et al. 2014). NER proficiency was correlated with cytogenetic characteristics, p53 status, sequencing data, gene expression profile, and with melphalan (MLP) sensitivity evaluated by CellTiterGlo (CTG). We then evaluated NER efficiency in patient samples and interrogated the role of NER in MM patients by correlating expression of NER genes with survival (OS) in a cohort of 170 patients (IFM 2005-01) homogeneously treated with alkylating agents. Results NER, measured as the amount of (6-4) photoproducts remaining 2 hours after UV irradiation, showed variability between MM cell lines. Out of 18 cell lines, 7 exhibited various levels of NER deficiencies, defined as less than 90% repair at 2 hours (4 cell lines 90-70% and 3 cell lines <60%). The other 11 cell lines presented more than 90% of repair. P53 loss of function did not associate with NER deficiency. Notably, all t(4;14) cell lines tested (n=5) showed a NER repair rate > 90%. NER deficient cell lines (NER <90%) were sensitive to melphalan. However all melphalan sensitive cells did not exhibit NER deficiency, This suggests that other DNA repair pathways are involved in the repair of melphalan-induced lesions. Furthermore, we performed the assay in patient samples showing variable levels of NER, which may reflect different disease status and prognosis. Whole genome sequencing data from 6 NER deficient cell lines revealed missense mutations in critical NER genes in 2 of these cell lines. MM1S and MM1R cells showed mutations in the Xeroderma Pigmentosum Complementation Group A (XPA) gene (mutation D70H), and MM1R was also mutated in the Cockayne syndrome, ERCC6 gene (mutation L682I). Gene expression profile comparison in 12 of these showed a positive correlation between expression of NER genes and NER efficiency. We next studied expression of 20 NER genes in 170 patients treated with high dose melphalan (IFM 2005-01). The analysis revealed a significant negative correlation between 5 overexpressed NER genes (ERCC3, ERCC4, ERCC6, MMS19 and NTHL1) and overall survival (OS). Conclusion NER efficiency is heterogeneous in MM, in part due to acquired mutations. Impairment of NER is associated with outcome as well as may contribute to genomic instability. Ability to proficiently measure NER in patient samples provides us an opportunity to now evaluate NER as a prognostic marker in myeloma. Disclosures No relevant conflicts of interest to declare.

scholarly journals H. pylori -Induced DNA Strand Breaks Are Introduced by Nucleotide Excision Repair Endonucleases and Promote NF-κB Target Gene Expression

Cell Reports ◽  
2015 ◽  
Vol 13 (1) ◽  
pp. 70-79 ◽  
Author(s):  
Mara L. Hartung ◽  
Dorothea C. Gruber ◽  
Katrin N. Koch ◽  
Livia Grüter ◽  
Hubert Rehrauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nucleotide Excision Repair ◽  
Target Gene ◽  
Excision Repair ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Target Gene Expression ◽  
Nucleotide Excision ◽  
Dna Strand ◽  
H Pylori

Abstract 3938: Altered nucleotide excision repair gene expression after cisplatin treatment in melanoma

2010 ◽  
Author(s):  
Nikola A. Bowden ◽  
Katie A. Ashton ◽  
Kelly A. Avery-Kiejda ◽  
Xu Dong Zhang ◽  
Peter Hersey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Repair Gene ◽  
Nucleotide Excision Repair Gene ◽  
Nucleotide Excision

scholarly journals Roles ofBacillus subtilisRecA, Nucleotide Excision Repair, and Translesion Synthesis Polymerases in Counteracting Cr(VI)-Promoted DNA Damage

2019 ◽  
Vol 201 (8) ◽  
Author(s):  
Fernando Santos-Escobar ◽  
Hilda C. Leyva-Sánchez ◽  
Norma Ramírez-Ramírez ◽  
Armando Obregón-Herrera ◽  
Mario Pedraza-Reyes
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Translesion Synthesis ◽  
Sos Response ◽  
Genotoxic Effects ◽  
Content Type ◽  
Nucleotide Excision

ABSTRACTBacteria deploy global programs of gene expression, including components of the SOS response, to counteract the cytotoxic and genotoxic effects of environmental DNA-damaging factors. Here we report that genetic damage promoted by hexavalent chromium elicited the SOS response inBacillus subtilis, as evidenced by the induction of transcriptionaluvrA-lacZ,recA-lacZ, and PrecA-gfpfusions. Accordingly,B. subtilisstrains deficient in homologous recombination (RecA) and nucleotide excision repair (NER) (UvrA), components of the SOS response, were significantly more sensitive to Cr(VI) treatment than were cells of the wild-type strain. These results strongly suggest that Cr(VI) induces the formation in growingB. subtiliscells of cytotoxic and genotoxic bulky DNA lesions that are processed by RecA and/or the NER pathways. In agreement with this notion, Cr(VI) significantly increased the formation of DNA-protein cross-links (DPCs) and induced mutagenesis inrecA- anduvrA-deficientB. subtilisstrains, through a pathway that required YqjH/YqjW-mediated translesion synthesis. We conclude that Cr(VI) promotes mutagenesis and cell death inB. subtilisby a mechanism that involves the formation of DPCs and that such deleterious effects are counteracted by both the NER and homologous recombination pathways, belonging to the RecA-dependent SOS system.IMPORTANCEIt has been shown that, following permeation of cell barriers, Cr(VI) killsB. subtiliscells following a mechanism of reactive oxygen species-promoted DNA damage, which is counteracted by the guanine oxidized repair system. Here we report a distinct mechanism of Cr(VI)-promoted DNA damage that involves production of DPCs capable of eliciting the bacterial SOS response. We also report that the NER and homologous recombination (RecA) repair pathways, as well as low-fidelity DNA polymerases, counteract this metal-induced mechanism of killing inB. subtilis. Hence, our results contribute to an understanding of how environmental pollutants activate global programs of gene expression that allow bacteria to contend with the cytotoxic and genotoxic effects of heavy metals.

scholarly journals Preliminary Evidence for a Hormetic Effect on DNA Nucleotide Excision Repair in Veterans with Gulf War Illness

2019 ◽  
Vol 185 (1-2) ◽  
pp. e47-e52 ◽  
Author(s):  
Jean J Latimer ◽  
Abdullah Alhamed ◽  
Stefanie Sveiven ◽  
Ali Almutairy ◽  
Nancy G Klimas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Gulf War ◽  
Gulf War Illness ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Persistent Symptoms ◽  
Nucleotide Excision

Abstract Introduction Veterans of the 1991 Gulf War were potentially exposed to a mixture of stress, chemicals and radiation that may have contributed to the persistent symptoms of Gulf War Illness (GWI). The genotoxic effects of some of these exposures are mediated by the DNA nucleotide excision repair (NER) pathway. We hypothesized that individuals with relatively low DNA repair capacity would suffer greater damage from cumulative genotoxic exposures, some of which would persist, causing ongoing problems. Materials and Methods Blood samples were obtained from symptomatic Gulf War veterans and age-matched controls. The unscheduled DNA synthesis assay, a functional measurement of NER capacity, was performed on cultured lymphocytes, and lymphocyte mRNA was extracted and analyzed by sequencing. Results Despite our hypothesis that GWI would be associated with DNA repair deficiency, NER capacity in lymphocytes from affected GWI veterans actually exhibited a significantly elevated level of DNA repair (p = 0.016). Both total gene expression and NER gene expression successfully differentiated individuals with GWI from unaffected controls. The observed functional increase in DNA repair capacity was accompanied by an overexpression of genes in the NER pathway, as determined by RNA sequencing analysis. Conclusion We suggest that the observed elevations in DNA repair capacity and NER gene expression are indicative of a “hormetic,” i.e., induced or adaptive protective response to battlefield exposures. Normally such effects are short-term, but in these individuals this response has resulted in a long-term metabolic shift that may also be responsible for the persistent symptoms of GWI.

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