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DNA repair drives cisplatin-induced neuronal death [RNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329931 | GEO | 2026/06/10

REPOSITORIES: GEO

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DNA repair drives cisplatin-induced neuronal death [END-seq]

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

DNA repair drives cisplatin-induced neuronal death [SAR-seq]

2026-06-10 | GSE329933 | GEO

DNA repair drives cisplatin-induced neuronal death

Project description:Cisplatin and similar 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 neurotoxicities, 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 DNA 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 (dN) or genetic upregulation of dNTP production protects neurons from cisplatin-induced cell death. 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.

2026-04-28 | GSE329361 | GEO

Metabolic clogging of mannose in human cancer cells triggers genome instability via dNTP loss

Project description:Mannose is an anti-cancer sugar that inhibits cell proliferation and enhances chemotherapy. How mannose exerts its anti-cancer activities, however, remains poorly understood. Here, using genetically engineered human cancer cells that permit the precise control of mannose metabolic flux, we demonstrate that the large influx of mannose exceeding its metabolic capacity induced a global metabolic remodeling, leading to the generation of slow-cycling cells with limited deoxyribonucleoside triphosphate (dNTP) pools. This metabolic remodeling impaired dormant origin firing required to rescue stalled forks by cisplatin, thus exacerbating replication stress. Importantly, a pharmacological inhibition of de novo dNTP biosynthesis was sufficient to sensitize the non-engineered cells to cisplatin and inhibit dormant origin firing, suggesting the dNTP loss-induced genome instability as a major mechanism for the anti-cancer activities of mannose.

2023-07-06 | PXD036449 | Pride

Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting

Project description:Homologous recombination (HR) and nucleotide excision repair (NER) are the two most frequently disabled DNA repair pathways in cancer. HR-deficient breast, ovarian, pancreatic and prostate cancers respond well to platinum chemotherapy and PARP inhibitors. However, the frequency of HR deficiency in gastric and esophageal adenocarcinoma (GEA) still lacks diagnostic and functional validation. Using whole exome and genome sequencing data, we found that a significant subset of GEA, but very few colorectal adenocarcinomas, show evidence of HR deficiency by mutational signature analysis (HRD score). High HRD gastric cancer cell lines demonstrated functional HR deficiency by RAD51 foci assay and increased sensitivity to platinum chemotherapy and PARP inhibitors. Of clinical relevance, analysis of three different GEA patient cohorts demonstrated that platinum treated HR deficient cancers had better outcomes. A gastric cancer cell line with strong sensitivity to cisplatin showed HR proficiency but exhibited NER deficiency by two photoproduct repair assays. Single-cell RNA-sequencing revealed that, in addition to inducing apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, validated by intracellular GSH assay. Overall, our study provides preclinical evidence that a subset of GEAs harbor genomic features of HR and NER deficiency and may therefore benefit from platinum chemotherapy and PARP inhibitors.

2024-02-23 | GSE256301 | GEO

Cisplatin treated melanoma and melanocyte cell lines

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2013-07-01 | GSE47980 | GEO

Ribonucleotides incorporated by the yeast mitochondrial DNA polymerase are not repaired

Project description:Misincorporation of ribonucleotides into DNA during genome replication has recently become recognized as a significant source of genomic instability. The frequency of ribonucleotides in the genome is determined by dNTP/rNTP ratios, the ability of the DNA polymerases to discriminate against ribonucleotides, and by the capacity of repair mechanisms to remove misincorporated ribonucleotides. To simultaneously compare how the nuclear and mitochondrial genomes incorporate and remove ribonucleotides, we challenged these processes by imbalancing cellular dNTP pools. Using a collection of yeast strains with altered dNTP pools, we discovered an inverse relationship between the concentration of individual dNTPs and the amount of the corresponding ribonucleotides incorporated in mitochondrial DNA, while in nuclear DNA the ribonucleotide pattern was only altered in the absence of ribonucleotide excision repair. Our analysis uncovers major differences in ribonucleotide repair between the two genomes and provides concrete evidence that yeast mitochondria lack mechanisms for repair of misincorporated ribonucleotides.

2017-11-07 | GSE100352 | GEO

Removal of oxaliplatin- and cisplatin-DNA lesions requires different global genome repair mechanisms that affect their clinical efficacy.

Project description:The therapeutical efficacy of cisplatin and oxaliplatin depends on the balance between the DNA damage induction and the DNA damage response of tumor cells. Based on clinical evidence, oxaliplatin is administered to cisplatin-unresponsive cancers, but the underlying molecular causes for this tumor specificity are not clear. Hence, stratification of patients based on DNA repair profiling is not sufficiently utilized for treatment selection. Using a combination of genetic, transcriptomic and imaging approaches, we identified factors that promote global genome nucleotide excision repair (GG-NER) of DNA-platinum adducts induced by oxaliplatin, but not by cisplatin. We show that oxaliplatin-DNA lesions are a poor substrate for GG-NER initiating factor XPC and that DDB2 and HMGA2 are required for efficient binding of XPC to oxaliplatin lesions and subsequent GG-NER initiation. Loss of DDB2 and HMGA2 therefore leads to hypersensitivity to oxaliplatin but not to cisplatin. As a result, low DDB2 levels in different colon cancer cells are associated with GG-NER deficiency and oxaliplatin hypersensitivity. Finally, we show that colon cancer patients with low DDB2 levels have a better prognosis after oxaliplatin treatment than patients with high DDB2 expression. We therefore propose that DDB2 is a promising predictive marker of oxaliplatin treatment efficiency in colon cancer.

2023-12-14 | GSE227871 | GEO

Gene expression of fibroblasts carrying SAMHD1 mutations or not

Project description:In mammalian cells, the catabolic activity of the dNTP triphosphohydrolase SAMHD1 sets the balance and the concentrations of the four dNTPs. Deficiency of SAMHD1 leads to unequally increased pools and marked dNTP imbalance. Although it is documented that imbalanced dNTP pool expansion increases mutation frequency in cancer cells, it is not known if the SAMHD1-induced dNTP imbalance favors accumulation of somatic mutations in non-transformed cells. Here we have investigated how fibroblasts isolated from Aicardi Goutières Syndrome (AGS) patients with mutated SAMHD1 react to the constitutive pool imbalance characterized by a huge dGTP pool. We focused on the effects on dNTP pools, cell-cycle progression, dynamics and fidelity of DNA replication, efficiency of UV-induced DNA repair. AGS fibroblasts entered senescence prematurely or upregulated genes involved in G1/S transition and DNA replication. The normally growing AGS cells exhibited unchanged DNA replication dynamics and, when quiescent, faster rate of excision repair of UV-induced DNA damages than wildtype fibroblasts. To investigate if the lack of SAMHD1 affects DNA replication fidelity we compared de novo mutations in AGS and WT cells by exome next generation sequencing. Somatic variant analysis indicated a mutator phenotype suggesting that SAMHD1 is a caretaker gene whose deficiency is per se mutagenic promoting genome instability in non-transformed cells.

2019-12-03 | GSE135652 | GEO

Nucleotide pools dictate the identity and frequency of ribonucleotide incorporation in mitochondrial DNA

Project description:Previous work has demonstrated the presence of ribonucleotides in human mitochondrial DNA (mtDNA) and in the present study we use a genome-wide approach to precisely map the location of these. We find that ribonucleotides are distributed evenly between the heavy- and light-strand of mtDNA. The relative levels of incorporated ribonucleotides reflect that DNA polymerase γ discriminates the four ribonucleotides differentially during DNA synthesis. The observed pattern is also dependent on the mitochondrial deoxyribonucleotide (dNTP) pools and disease-causing mutations that change these pools alter both the absolute and relative levels of incorporated ribonucleotides. Our analyses strongly suggest that DNA polymerase γ-dependent incorporation is the main source of ribonucleotides in mtDNA and argues against the existence of a mitochondrial ribonucleotide excision repair pathway in human cells. Furthermore, we clearly demonstrate that when dNTP pools are limiting, ribonucleotides serve as a source of building blocks to maintain DNA replication and genome stability. Increased levels of embedded ribonucleotides in patient cells with disturbed nucleotide pools may constitute to a pathogenic mechanism that affects mtDNA stability and impair new rounds of mtDNA replication

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