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Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

ABSTRACT: Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

PROVIDER: PRJNA1172681 | ENA |

REPOSITORIES: ENA

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Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

Project description:Temozolomide kills cancer cells by forming O6-methylguanine (O6-MeG), which leads to cell cycle arrest and apoptosis. However, O6-MeG repair by O6-methylguanine-DNA methyltransferase (MGMT) contributes to drug resistance. Characterizing genomic profiles of O6-MeG could elucidate how O6-MeG accumulation is influenced by repair, but there are no methods to map genomic locations of O6-MeG. Here, we developed an immunoprecipitation- and polymerase-stalling-based method, termed O6-MeG-seq, to locate O6-MeG across the whole genome at single-nucleotide resolution. We analyzed O6-MeG formation and repair with regards to sequence contexts and functional genomic regions in glioblastoma-derived cell lines and evaluated the impact of MGMT. O6-MeG signatures were highly similar to mutational signatures from patients previously treated with temozolomide. Furthermore, MGMT did not preferentially repair O6-MeG with respect to sequence context, chromatin state or gene expression level, however, may protect oncogenes from mutations. Finally, we found an MGMT-independent strand bias in O6-MeG accumulation in highly expressed genes in TMZ-exposed cells and naked DNA proposing an indirect influence of transcription to O6-MeG formation. These data provide high resolution insight on how O6-MeG formation and repair is impacted by genome structure and nucleotide sequence. Further, O6-MeG-seq is expected to enable future studies of DNA modification signatures as diagnostic markers for addressing drug resistance and preventing secondary cancers.

2024-10-30 | GSE279423 | GEO

Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

Project description:Temozolomide kills cancer cells by forming O6-methylguanine (O6-MeG), which leads to apoptosis due to mismatch-repair overload. However, O6-MeG repair by O6-methylguanine-DNA methyltransferase (MGMT) contributes to drug resistance. Genomic profiles of O6-MeG could elucidate how O6-MeG accumulation is influenced by repair mechanisms, but there are no methods to map genomic locations of O6-MeG. Here, we developed an immunoprecipitation- and polymerase-stalling-based method, termed O6-MeG-seq, to locate O6-MeG across the whole genome at single-nucleotide resolution. We analyzed O6-MeG formation and repair with regards to sequence contexts and functional genomic regions in glioblastoma-derived cell lines and evaluated the impact of MGMT transfection. O6-MeG signatures were highly similar to mutational signatures of patients previously treated with temozolomide. Furthermore, MGMT did not preferentially repair O6-MeG with respect to sequence context, chromatin state or gene expression level, however, may protect oncogenes from mutations. Finally, we found an MGMT-independent strand bias in O6-MeG accumulation in highly expressed genes, suggesting an additional transcription-associated contribution to its repair. These data provide high resolution insight on how O6-MeG formation and repair is impacted by genome structure and regulation. Further, O6-MeG-seq is expected to enable future studies of DNA modification signatures as diagnostic markers for addressing drug resistance and preventing secondary cancers.

2023-12-12 | GSE249155 | GEO

Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

Project description:Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

| PRJNA1047565 | ENA

Plasma Mouse LC-MSMS - Bortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survival

Project description:Patients diagnosed with glioblastoma (GBM) with sustained synthesis of the DNA repair enzyme, O6-methyl guanine DNA methytransferase (MGMT), are rendered resistant to Temozolomide (TMZ) chemotherapy. Here, we hypothesized that pretreatment with the proteasome inhibitor Bortezomib (BTZ, Velcade) might sensitize these GBM to TMZ by depleting MGMT.

2019-08-20 | PXD007193 | Pride

Gene profile of glioblastoma cells treated with y15 and temozolomide

Project description:The gene expression profiles were identified in glioblastoma cells treated with FAK inhibitor Y15, temozolomide alone or with combination of Y15 and Temozolomide DBTRG and U87 were treated with FAK inhibitor Y15 at 10 microM for 24 h; U87 cells were treated with Temozolomide 100 microM for 24 h and Y15+temozolomide at the same dose as each agent alone

2013-01-12 | E-GEOD-43452 | biostudies-arrayexpress

Pseudomonas chlororaphis O6 strain:O6

Project description:Pseudomonas chlororaphis O6 genome sequencing

| PRJNA67531 | ENA

Proteomics of Temozolomide for Glioblastoma

Project description:Using the human glioblastoma cell line LN229, temozolomide was used to detect proteome changes and identify critical components regulating chemotherapy sensitivity.

2023-05-17 | PXD042080 | Pride

A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma

Project description:Temozolomide (TMZ) has been used for the treatment of glioblastoma (GBM) since last decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that a novel enhancer, located between the promoters of Ki67 and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines as well as in recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to reduced levels of MGMT and Ki67, increased TMZ sensitivity and impaired proliferation. Together, these studies uncover a novel mechanism that regulates MGMT expression, confers TMZ resistance and potentially regulates tumor proliferation.

2018-07-13 | GSE113816 | GEO

Gene profile of glioblastoma cells treated with y15 and temozolomide

Project description:The gene expression profiles were identified in glioblastoma cells treated with FAK inhibitor Y15, temozolomide alone or with combination of Y15 and Temozolomide

2013-01-12 | GSE43452 | GEO

Single-nucleotide resolution dynamic repair maps of UV damage in Saccharomyces cerevisiae genome

Project description:We have adapted the eXcision Repair-sequencing (XR-seq) method to generate single-nucleotide resolution dynamic repair maps of UV-induced cyclobutane pyrimidine dimers (CPDs) and (6-4) pyrimidine-pyrimidone photoproducts [(6-4)PPs] in the Saccharomyces cerevisiae genome. We find that these photoproducts are removed from the genome primarily by incisions 13-18 nucleotides 5’ and 6-7 nucleotides 3’ to the UV damage that generate 21-27 nt-long excision products. Analyses of the excision repair kinetics both in single genes and at the genome-wide level reveal strong transcription-coupled repair of the transcribed strand (TS) at early time points followed by predominantly non-transcribed strand (NTS) repair at later stages. We have also characterized the excision repair level as a function of transcription level. The availability of high-resolution and dynamic repair maps should aid in future repair and mutagenesis studies in this model organism.

2018-04-12 | GSE110621 | GEO

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