Cisplatin-DNA Adduct Repair of Transcribed Genes is Controlled by Two Circadian Programs in Mouse Tissues
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PROVIDER: PRJNA432384 | ENA |
REPOSITORIES: ENA
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Project description:We tested the impact of clock time on excision repair of cisplatin-induced DNA damage at single nucleotide resolution across the genome in mouse liver and kidney. We found that genome repair is controlled by two circadian programs.
2018-06-21 | GSE109938 | GEO
Project description: Not available
| S-EPMC6003508 | biostudies-literature
Project description:Cisplatin is the most commonly used chemotherapeutic drug for treating solid tumors. However, its toxicity and the innate or acquired resistance of cancer cells to the drug limit its usefulness. Cisplatin kills cells by forming cisplatin-DNA adducts, most commonly in the form of Pt-d(GpG) diadduct. We recently showed that repair of this adduct within 2 hours following injection is controlled by two circadian programs: (1) The circadian clock controls transcription of 2000 genes in mouse liver and thereby controls repair of the transcribed strand of these genes via transcription coupled repair in a rhythmic fashion unique to each gene’s phase of transcription. (2) The basal excision repair activity itself is controlled by the circadian clock with a single phase at which the repair of the non-transcribed strand and the rest of the genome take place. Here, we have followed the repair kinetic for long periods genome-wide both globally and at single nucleotide resolution by the Excision Repair-sequencing (XR-seq) method to gain further insight into cisplatin DNA damage and repair with the aim of improving the therapeutic index of the drug. Our data show that transcription-driven repair is complete after two days, while completion of basal repair of nontranscribed strands, silent genes and intergenic regions requires weeks. In rhythmically controlled genes, oscillations of transcribed repair are observed up to 2 days post-injection, and in both constitutively transcribed and rhythmic genes, we see a trend in template strand repair with time from the 5’to 3’ end. These findings add to the complexity of circadian- and transcription-dependent and -independent control of repair exhibited by this model organism in response to cisplatin.
2019-06-24 | GSE132002 | GEO
Project description:Cisplatin is the most commonly used chemotherapeutic drug for treating solid tumors. However, its toxicity and the innate or acquired resistance of cancer cells to the drug limit its usefulness. Cisplatin kills cells by forming cisplatin-DNA adducts, most commonly in the form of Pt-d(GpG) diadduct. We recently showed that repair of this adduct within 2 hours following injection is controlled by two circadian programs: (1) The circadian clock controls transcription of 2000 genes in mouse liver and thereby controls repair of the transcribed strand of these genes via transcription coupled repair in a rhythmic fashion unique to each gene’s phase of transcription. (2) The basal excision repair activity itself is controlled by the circadian clock with a single phase at which the repair of the non-transcribed strand and the rest of the genome take place. Here, we have followed the repair kinetic for long periods genome-wide both globally and at single nucleotide resolution by the Excision Repair-sequencing (XR-seq) method to gain further insight into cisplatin DNA damage and repair with the aim of improving the therapeutic index of the drug. Our data show that transcription-driven repair is complete after two days, while completion of basal repair of nontranscribed strands, silent genes and intergenic regions requires weeks. In rhythmically controlled genes, oscillations of transcribed repair are observed up to 2 days post-injection, and in both constitutively transcribed and rhythmic genes, we see a trend in template strand repair with time from the 5’to 3’ end. These findings add to the complexity of circadian- and transcription-dependent and -independent control of repair exhibited by this model organism in response to cisplatin.
2019-06-24 | GSE132993 | GEO
Project description:We used the recently developed Excision Repair-sequencing (XR-seq) method to study genome-wide repair of UV-induced DNA damage in Arabidopsis. We found that the repair of cyclobutane pyrimidine dimers for a large fraction of the genome is controlled by the joint actions of the circadian clock and transcription by RNA polymerase II. Arabidopsis has a relatively compact genome, and a large fraction of the genes are controlled by the circadian clock. Our data on the interface of these two global regulatory systems reveal very strong repair preference of the transcribed strands of Arabidopsis genes, 10 to 30% of which are circadian time-dependent. Thus, throughout the day, Arabidopsis exhibits enormous dynamic range in repair to cope with exposure to sunlight.
2018-04-17 | GSE108932 | GEO
Project description:Platinum-based drug cisplatin is a widely used first-line therapy for several cancers. Cisplatin interacts with DNA mainly in the form of Pt-d(GpG) di-adduct, which stalls cell proliferation and activates DNA damage response pathway. Cisplatin DNA-adducts are primarily repaired by nucleotide excision repair system. Despite cisplatin shows a broad spectrum of anticancer activity, it has limitation of use due to acquired drug resistance and toxicity to nontargeted tissues. By integrating genome-wide high-throughput “damage-seq”, “XR-seq”, mRNA-seq approaches along with epigenomic data we studied the mechanism of action of cisplatin across the mouse genome in kidney, liver, lung and spleen. Genome-wide damage-seq data reveal that kidney is highest cisplatin-damage accumulation site, while spleen is lowest. Excision repair on transcribed strand (TS) and non-transcribed strand (NTS) in active genes is in positive correlation with gene transcription, and regarding to nucleotide excision repair efficiency, there is no significant difference across organs. Lastly, in response to cisplatin treatment ATM signaling is upregulated in kidney, liver and lung, while PKA signaling is downregulated across all organs. The methodology and data we presented here include four different mouse organs and three “omics” data, it unbiasedly constitutes a foundation for understanding the mechanism of cellular respond to cisplatin and by means of improving chemotherapy while reducing side effect to normal tissues.
2019-01-01 | GSE117167 | GEO
Project description:Cisplatin is one of the most potent chemotherapy drugs to treat cancers, but its clinical application remains limited due to severe nephrotoxicity. Several approaches have been developed to minimize such side effects, notably including chronotherapy, a well-known strategy based on the circadian clock. However, the component of the circadian clock machinery that particularly responses to the cisplatin stimulation remains unknown, including its functions in cisplatin-induced renal injury. In our present study, we demonstrated that Bmal1, as a key clock gene, was induced by the cisplatin stimulation in the mouse kidney and cultured human HK-2 renal cells. Gain- and loss-of-function studies indicated that Bmal1 facilitated cisplatin-induced renal injury both in vivo and in vitro, by aggravating the cell apoptotic process. More importantly, RNA-seq analysis revealed that Bmal1 triggered the expression of hallmark genes involved in renal hepatization, a critical event accompanied by the injury. At the molecular level, Bmal1 activated the transcription of hepatization-associated genes through direct recruitment to the E-box motifs of their promoters. Our findings suggest that Bmal1, a pivotal mediator induced renal injury in response to cisplatin treatment, and the therapeutic intervention targeting Bmal1 in the kidney may be a promising strategy to minimize the toxic side-effects of cisplatin in its clinical applications.
2020-04-24 | GSE149172 | GEO
Project description:Disentangaling the gene expression programs controlled by ciliary and cytosolic cAMP signaling
| PRJNA755958 | ENA
Project description:We used Affymetrix microarrays to determine the cisplatin-induced gene expression changes in E. coli deficient in dam and mismatch repair (dam, dam mutS, and mutS mutant strains). E. coli deficient in dam are hypersensitive to cisplatin. However introducing an additional mutation in mismatch repair (i.e., a mutation in mutS or mutL) abrogates this sensitivity and essentially restores wildtype levels of resistance. Keywords: Drug-induced expression
2005-07-27 | GSE2999 | GEO
Project description:Chemotherapeutic use of cisplatin is limited by its severe side effects. In this study, we demonstrated that cisplatin induces cell death in a proximal tubular cell line by suppressing glycolysis- and tricarboxylic acid (TCA)/mitochondria-related genes. HK-2 cells were cultured to confluence in 100mm dishes. Total RNA was extracted (QIAGEN, Valencia, CA, USA), and the concentration in the samples was measured using a Micro UV-Vis fluorescence spectrophotometer (Malcom, Tokyo, JAPAN). Sample of 10ɥg of Total RNA from HK-2 cells were labeled with biotin (3'IVT Labeling Kit, Affymetrix, USA) and hybridized (GeneAtlas Hybridization, Wash, and Stain Kit for 3' IVT Arrays, Affymetrix). The Microarray platform used was Affymetrix HG U219 Array Strip. The arrays were scanned in a GeneAtlas scanner controlled by GeneAtlas Software (Affymetrix, Sta. Clara, USA). Genes were later filtered according to expression fold change (Affymetrix Expression Console software, Affymetrix) Using Affymetrix GeneAtlas System, we determined the gene expression profiles of HK-2 cells treated with cisplatin. Two replicates were made for each timepoints (control, 6h and 24h).
2015-06-09 | E-GEOD-69644 | biostudies-arrayexpress