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Cisplatin-DNA Adduct Repair of Transcribed Genes is Controlled by Two Circadian Programs in Mouse Tissues

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE109938 | GEO | 2018/06/21

REPOSITORIES: GEO

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Long-Term Kinetic Analysis of the Effect of the Circadian Clock and Transcription on Repair of Cisplatin-DNA Adducts in Mouse Liver

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

Long-term, genome-wide kinetic analysis of the effect of the circadian clock and transcription on the repair of cisplatin-DNA adducts in the mouse liver

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Circadian Clock- and Transcription-controlled Genome-wide Excision Repair of UV Damage in Arabidopsis

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

Cisplatin-DNA Adduct Repair of Transcribed Genes is Controlled by Two Circadian Programs in Mouse Tissues

Project description:Cisplatin-DNA Adduct Repair of Transcribed Genes is Controlled by Two Circadian Programs in Mouse Tissues

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Cisplatin-DNA adduct repair of transcribed genes is controlled by two circadian programs in mouse tissues.

Project description:Cisplatin is a major cancer chemotherapeutic drug. It kills cancer cells by damaging their DNA, mainly in the form of Pt-d(GpG) diadducts. However, it also has serious side effects, including nephrotoxicity and hepatotoxicity that limit its usefulness. Chronotherapy is taking circadian time into account during therapy to improve the therapeutic index, by improving efficacy and/or limiting toxicity. To this end, we tested the impact of clock time on excision repair of cisplatin-induced DNA damage at single-nucleotide resolution across the genome in mouse kidney and liver. We found that genome repair is controlled by two circadian programs. Repair of the transcribed strand (TS) of active, circadian-controlled genes is dictated by each gene's phase of transcription, which falls across the circadian cycle with prominent peaks at dawn and dusk. In contrast, repair of the nontranscribed strand (NTS) of all genes, repair of intergenic DNA, and global repair overall peaks at Zeitgeber time ZT08, as basal repair capacity, which is controlled by the circadian clock, peaks at this circadian time. Consequently, the TS and NTS of many genes are repaired out of phase. As most cancers are thought to have defective circadian rhythms, these results suggest that future research on timed dosage of cisplatin could potentially reduce damage to healthy tissue and improve its therapeutic index.

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Cisplatin DNA Damage and Repair Maps of the Human Genome at Single-nucleotide Resolution

Project description:Platinum chemotherapies induce damages in DNA that distort the helical structure. In human cells, these adducts are removed primarily by the Nucleotide Excision Repair pathway. In this study, we mapped both cisplatin and oxaliplatin induced damages and their repair at single nucleotide resolution across the human genome.

2016-09-16 | GSE82213 | GEO

Genome-wide repair maps of nucleotide excision repair in Drosophila and S2 cells.

Project description:We report the application of single-molecule-based sequencing technology (XR-seq) for high-throughput profiling of nucleotide excision repair in Drosophila four developmental stages and S2 cells. By obtaining over six billion bases of sequence from UV and cisplatin damage antibodies immunoprecipitated excision DNA, we generated genome-wide nucleotide excision repair maps of Drosophila Embryo, Larva, Pupa , two gender of adults and S2 cells . We find that Drosophila performs transcription-coupled repair (TCR) at all its developmental stages. S2 cell carry out TCR response to both UV and Cisplatin damage. Finally, we show that XPC repair factor is required for both global and transcription-coupled repair in Drosophila. This study provides the mechanism of nucleotide excision repair of Drosophila in vivo and vitro response to UV and Cisplatin damage.

2022-02-25 | GSE184926 | GEO

Tissue-specific transcriptomic and epigenomic profiles explain differential damage and repair of anti-cancer drug cisplatin induced DNA-adducts across mouse organs

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

Circadian Clock- and Transcription-controlled Genome-wide Excision Repair of UV Damage in Arabidopsis

Project description:Circadian Clock- and Transcription-controlled Genome-wide Excision Repair of UV Damage in Arabidopsis

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Cisplatin treated melanoma and melanocyte cell lines

Project description:Nucleotide excision repair (NER) orchestrates the repair of helix distorting DNA damage, induced by both ultraviolet radiation (UVR) and cisplatin. There is evidence that the global genome repair (GGR) arm of NER is dysfunctional in melanoma and it is known to have limited induction in melanoma cell lines after cisplatin treatment. The aims of this study were to examine mRNA transcript levels of regulators of GGR and to investigate the downstream effect on global transcript expression in melanoma cell lines after cisplatin treatment and in melanoma tumours.

2013-07-01 | GSE47980 | GEO

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