Cisplatin-DNA Adduct Repair of Transcribed Genes is Controlled by Two Circadian Programs in Mouse Tissues
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE109938 | GEO | 2018/06/21
REPOSITORIES: GEO
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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: Not available
| S-EPMC6003508 | biostudies-literature
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:Cisplatin-DNA Adduct Repair of Transcribed Genes is Controlled by Two Circadian Programs in Mouse Tissues
| PRJNA432384 | ENA
Project description:Cisplatin and similar-acting alkylating chemotherapy agents are the cornerstone treatments for many types of cancers. While effective, these drugs induce long-term side-effects in post-mitotic tissues including the nervous system. There are no known effective pharmacological interventions for chemotherapy-induced neurotoxicity, in part due to our limited understanding of how neurons and other non-dividing cells respond to DNA damage. Here, we show that nucleotide excision repair (NER) is responsible for cisplatin adduct removal in human neurons. However, contrary to its protective role in dividing cells, NER drives neuronal cell death in response to cisplatin. Through excision repair synthesis, NER exhausts low levels of deoxynucleoside triphosphate (dNTP) pools found in post-mitotic neurons. dNTP pools are first consumed to resolve transcription-blocking lesions through transcription-coupled NER. When dNTPs become exhausted, toxic double-strand breaks accumulate across the genome primarily because of incomplete global-genome NER. Supplementation with deoxynucleosides through pharmacological or genetic means protects neurons from cisplatin-induced cell death and reduces cisplatin-induced neuropathic pain in mice. These results identify low levels of endogenous dNTP pools as a vulnerability of post-mitotic cells to DNA damage and suggest nucleoside supplementation as a strategy to protect patients from chemotherapy-induced neurotoxicity.
2026-06-10 | GSE329933 | GEO
Project description:Cisplatin and similar-acting alkylating chemotherapy agents are the cornerstone treatments for many types of cancers. While effective, these drugs induce long-term side-effects in post-mitotic tissues including the nervous system. There are no known effective pharmacological interventions for chemotherapy-induced neurotoxicity, in part due to our limited understanding of how neurons and other non-dividing cells respond to DNA damage. Here, we show that nucleotide excision repair (NER) is responsible for cisplatin adduct removal in human neurons. However, contrary to its protective role in dividing cells, NER drives neuronal cell death in response to cisplatin. Through excision repair synthesis, NER exhausts low levels of deoxynucleoside triphosphate (dNTP) pools found in post-mitotic neurons. dNTP pools are first consumed to resolve transcription-blocking lesions through transcription-coupled NER. When dNTPs become exhausted, toxic double-strand breaks accumulate across the genome primarily because of incomplete global-genome NER. Supplementation with deoxynucleosides through pharmacological or genetic means protects neurons from cisplatin-induced cell death and reduces cisplatin-induced neuropathic pain in mice. These results identify low levels of endogenous dNTP pools as a vulnerability of post-mitotic cells to DNA damage and suggest nucleoside supplementation as a strategy to protect patients from chemotherapy-induced neurotoxicity.
2026-06-10 | GSE329931 | GEO
Project description:Cisplatin and similar-acting alkylating chemotherapy agents are the cornerstone treatments for many types of cancers. While effective, these drugs induce long-term side-effects in post-mitotic tissues including the nervous system. There are no known effective pharmacological interventions for chemotherapy-induced neurotoxicity, in part due to our limited understanding of how neurons and other non-dividing cells respond to DNA damage. Here, we show that nucleotide excision repair (NER) is responsible for cisplatin adduct removal in human neurons. However, contrary to its protective role in dividing cells, NER drives neuronal cell death in response to cisplatin. Through excision repair synthesis, NER exhausts low levels of deoxynucleoside triphosphate (dNTP) pools found in post-mitotic neurons. dNTP pools are first consumed to resolve transcription-blocking lesions through transcription-coupled NER. When dNTPs become exhausted, toxic double-strand breaks accumulate across the genome primarily because of incomplete global-genome NER. Supplementation with deoxynucleosides through pharmacological or genetic means protects neurons from cisplatin-induced cell death and reduces cisplatin-induced neuropathic pain in mice. These results identify low levels of endogenous dNTP pools as a vulnerability of post-mitotic cells to DNA damage and suggest nucleoside supplementation as a strategy to protect patients from chemotherapy-induced neurotoxicity.
2026-06-10 | GSE329929 | GEO
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
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