Mechanism of cytarabine-induced neurotoxicity [SAR-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE293253 | GEO | 2025/05/13
REPOSITORIES: GEO
Similar Datasets
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
2025-05-13 | GSE293255 | GEO
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
2025-05-13 | GSE293246 | GEO
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
2025-05-13 | GSE293247 | GEO
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
2025-05-13 | GSE293245 | GEO
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
2025-05-13 | GSE293252 | GEO
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
2025-05-13 | GSE293251 | GEO
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
2025-05-13 | GSE293250 | GEO
Project description:Postmitotic neurons are known to harbor high levels of methylated cytosine and its oxidized intermediates such as 5hmC, but the functional relevance of these epigenetic modifications of DNA are poorly understood. We show that some but not all cytidine analogs, such as cytarabine, cause DNA double strand breaks (DSB) during TET-mediated active 5mC demethylation by interrupting TDG-dependent base excision repair. These DSBs are frequently converted into indels and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage to cytarabine. In Purkinje cells, TET targets gene bodies with the highest expression marked by enhancer-associated histone modifications. Many of these genes control movement coordination which explains the long recognized cerebellar neurotoxicity of cytarabine. We show that other cytidine analogs, such as gemcitabine cause only single strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons and provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
2025-05-13 | GSE293248 | GEO
Project description:Neurons harbor high levels of endogenous single strand DNA breaks (SSBs) that are targeted to neuronal enhancers and correlate with marks of DNA demethylation. To determine the source of SSBs at neuronal enhancers, we depleted the thymidine DNA glycosylase TDG, which excises TET-mediated oxidized methylcytidines 5fC and 5caC, to produce unmodified C. In differentiating neurons, induced degradation of TDG led to the disappearance of SSBs, demonstrating the existence of ongoing TET‑mediated oxidation. Using an independent model of macrophage differentiation from reprogrammed pre-B cells, we demonstrate that TET/TDG-mediated active demethylation may be a general mechanism underlying post-mitotic lineage specification. We find that macrophage differentiation prefers short patch base excision repair (SP-BER) to fill-in single nucleotide gaps, whereas neurons also frequently utilize the long-patch (LP-BER) sub-pathway. By measuring the distribution of SSBs relative to sites of oxidized cytosine, we observed that stretches of 2-30 bases are synthesized distal from the methylated CpG site during repair. Disrupting gap-filling using anti-neoplastic nucleoside analogs resulted in continuous DNA damage/repair events at enhancers each resolving within 1-2 hours, but ultimately triggering neuronal cell death. This DNA damage response and toxicity was dependent on TDG activity. Thus, TET-mediated active DNA demethylation promotes endogenous DNA damage at regulatory elements, a process which normally contributes to cell identity but can also provoke neurotoxicity following anti-cancer treatments.
2022-12-01 | GSE210314 | GEO
Project description:Neurons harbor high levels of endogenous single strand DNA breaks (SSBs) that are targeted to neuronal enhancers and correlate with marks of DNA demethylation. To determine the source of SSBs at neuronal enhancers, we depleted the thymidine DNA glycosylase TDG, which excises TET-mediated oxidized methylcytidines 5fC and 5caC, to produce unmodified C. In differentiating neurons, induced degradation of TDG led to the disappearance of SSBs, demonstrating the existence of ongoing TET‑mediated oxidation. Using an independent model of macrophage differentiation from reprogrammed pre-B cells, we demonstrate that TET/TDG-mediated active demethylation may be a general mechanism underlying post-mitotic lineage specification. We find that macrophage differentiation prefers short patch base excision repair (SP-BER) to fill-in single nucleotide gaps, whereas neurons also frequently utilize the long-patch (LP-BER) sub-pathway. By measuring the distribution of SSBs relative to sites of oxidized cytosine, we observed that stretches of 2-30 bases are synthesized distal from the methylated CpG site during repair. Disrupting gap-filling using anti-neoplastic nucleoside analogs resulted in continuous DNA damage/repair events at enhancers each resolving within 1-2 hours, but ultimately triggering neuronal cell death. This DNA damage response and toxicity was dependent on TDG activity. Thus, TET-mediated active DNA demethylation promotes endogenous DNA damage at regulatory elements, a process which normally contributes to cell identity but can also provoke neurotoxicity following anti-cancer treatments.
2022-12-01 | GSE210316 | GEO