Targeting meiotic recombination 11 (MRE11) nuclease for personalization of epithelial ovarian cancer therapy [2]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA816329 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18330053_1.fastq.gz | Fastqsanger.gz | |||
| SRR18330053_2.fastq.gz | Fastqsanger.gz | |||
| SRR18330054_1.fastq.gz | Fastqsanger.gz | |||
| SRR18330054_2.fastq.gz | Fastqsanger.gz | |||
| SRR18330055_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Targeting meiotic recombination 11 (MRE11) nuclease for personalization of epithelial ovarian cancer therapy
| PRJNA673495 | ENA
Project description:Platinum resistance is a clinical challenge in ovarian cancer. Platinating agents induce DNA damage which activate Mre11 nuclease directed DNA damage signalling and response (DDR). Upregulation of DDR may promote chemotherapy resistance. Here we have comprehensively evaluated Mre11 in epithelial ovarian cancers. In clinical cohort that received platinum- based chemotherapy (n=331), Mre11 protein overexpression was associated with aggressive phenotype and poor progression free survival (PFS) (p=0.002). In the ovarian cancer genome atlas (TCGA) cohort (n=498), Mre11 gene amplification was observed in a subset of serous tumours (5%) which correlated highly with Mre11 mRNA levels (p<0.0001). Altered Mre11 levels was linked with genome wide alterations that can influence platinum sensitivity. At the transcriptomic level (n=1259), Mre11 overexpression was associated with poor PFS (p=0.003). ROC analysis showed an area under the curve (AUC) of 0.642 for response to platinum-based chemotherapy. Pre-clinically, Mre11 depletion by gene knock down or blockade by small molecule inhibitor (Mirin) reversed platinum resistance in ovarian cancer cells and in 3D spheroid models. Importantly, Mre11 inhibition was synthetically lethal in platinum sensitive XRCC1 deficient ovarian cancer cells and 3D-spheroids. Selective cytotoxicity was associated with DNA double strand break (DSB) accumulation, S-phase cell cycle arrest and increased apoptosis. We conclude that pharmaceutical development of Mre11 inhibitors is a viable clinical strategy for platinum sensitization and synthetic lethality in ovarian cancer.
2022-07-04 | GSE160540 | GEO
Project description:Platinum resistance is a clinical challenge in ovarian cancer. Platinating agents induce DNA damage which activate Mre11 nuclease directed DNA damage signalling and response (DDR). Upregulation of DDR may promote chemotherapy resistance. Here we have comprehensively evaluated Mre11 in epithelial ovarian cancers. In clinical cohort that received platinum- based chemotherapy (n=331), Mre11 protein overexpression was associated with aggressive phenotype and poor progression free survival (PFS) (p=0.002). In the ovarian cancer genome atlas (TCGA) cohort (n=498), Mre11 gene amplification was observed in a subset of serous tumours (5%) which correlated highly with Mre11 mRNA levels (p<0.0001). Altered Mre11 levels was linked with genome wide alterations that can influence platinum sensitivity. At the transcriptomic level (n=1259), Mre11 overexpression was associated with poor PFS (p=0.003). ROC analysis showed an area under the curve (AUC) of 0.642 for response to platinum-based chemotherapy. Pre-clinically, Mre11 depletion by gene knock down or blockade by small molecule inhibitor (Mirin) reversed platinum resistance in ovarian cancer cells and in 3D spheroid models. Importantly, Mre11 inhibition was synthetically lethal in platinum sensitive XRCC1 deficient ovarian cancer cells and 3D-spheroids. Selective cytotoxicity was associated with DNA double strand break (DSB) accumulation, S-phase cell cycle arrest and increased apoptosis. We conclude that pharmaceutical development of Mre11 inhibitors is a viable clinical strategy for platinum sensitization and synthetic lethality in ovarian cancer.
2022-07-04 | GSE198648 | GEO
Project description:Meiotic recombination is of central importance for the proper segregation of homologous chromosomes and is initiated by DNA double-strand breaks (DSB) that depend on Spo11 and Mre11. Calibrated chromatin immunoprecipitation (ChIP) for Mre11 shows that Spo11 promotes Mre11 recruitment to chromatin, independent of DSB formation. A C-terminal deletion mutant deficient in Spo11 interaction severely reduces the association of Mre11 with meiotic chromatin. Consistent with the reduction of Mre11 foci in this mutant, it strongly impedes DSB formation, leading to spore death.
2024-01-25 | GSE253302 | GEO
Project description:Nucleolytic resection of DNA ends is critical for homologous recombination, but its mechanism is not fully understood, particularly in mammalian meiosis. Here we examine roles of the conserved MRN complex (MRE11, RAD50, and NBS1) through genome-wide analysis of meiotic resection in mice with various MRN mutations, including several that cause chromosomal instability in humans. Meiotic DSBs form at elevated levels but remain unresected if Mre11 is conditionally deleted, thus MRN is required for both resection initiation and regulation of DSB numbers. Resection lengths are reduced to varying degrees in MRN hypomorphs or if MRE11 nuclease activity is attenuated in a conditional nuclease-dead Mre11 model. These findings unexpectedly establish that MRN is needed for longer-range extension of resection, not just resection initiation. Finally, resection defects are additively worsened by combining MRN and Exo1 mutations, and mice that are unable to initiate resection or have greatly curtailed resection lengths experience catastrophic spermatogenic failure. Our results elucidate multiple functions of MRN in meiotic recombination, uncover unanticipated relationships between short- and long-range resection, and establish the importance of resection for mammalian meiosis.
2024-05-06 | GSE266258 | GEO
Project description:Nucleolytic resection of DNA ends is critical for homologous recombination, but its mechanism is not fully understood, particularly in mammalian meiosis. Here we examine roles of the conserved MRN complex (MRE11, RAD50, and NBS1) through genome-wide analysis of meiotic resection in mice with various MRN mutations, including several that cause chromosomal instability in humans. Meiotic DSBs form at elevated levels but remain unresected if Mre11 is conditionally deleted, thus MRN is required for both resection initiation and regulation of DSB numbers. Resection lengths are reduced to varying degrees in MRN hypomorphs or if MRE11 nuclease activity is attenuated in a conditional nuclease-dead Mre11 model. These findings unexpectedly establish that MRN is needed for longer-range extension of resection, not just resection initiation. Finally, resection defects are additively worsened by combining MRN and Exo1 mutations, and mice that are unable to initiate resection or have greatly curtailed resection lengths experience catastrophic spermatogenic failure. Our results elucidate multiple functions of MRN in meiotic recombination, uncover unanticipated relationships between short- and long-range resection, and establish the importance of resection for mammalian meiosis.
2024-05-06 | GSE266271 | GEO
Project description:Nucleolytic resection of DNA ends is critical for homologous recombination, but its mechanism is not fully understood, particularly in mammalian meiosis. Here we examine roles of the conserved MRN complex (MRE11, RAD50, and NBS1) through genome-wide analysis of meiotic resection in mice with various MRN mutations, including several that cause chromosomal instability in humans. Meiotic DSBs form at elevated levels but remain unresected if Mre11 is conditionally deleted, thus MRN is required for both resection initiation and regulation of DSB numbers. Resection lengths are reduced to varying degrees in MRN hypomorphs or if MRE11 nuclease activity is attenuated in a conditional nuclease-dead Mre11 model. These findings unexpectedly establish that MRN is needed for longer-range extension of resection, not just resection initiation. Finally, resection defects are additively worsened by combining MRN and Exo1 mutations, and mice that are unable to initiate resection or have greatly curtailed resection lengths experience catastrophic spermatogenic failure. Our results elucidate multiple functions of MRN in meiotic recombination, uncover unanticipated relationships between short- and long-range resection, and establish the importance of resection for mammalian meiosis.
2024-05-06 | GSE266151 | GEO
Project description:Mre11, together with Rad50 and Xrs2/NBS, plays pivotal roles in homologous recombination, repair of DNA double strand breaks (DSBs), activation of damage-induced checkpoint, and telomere maintenance. Using DNA microarray assays to analyze yeast mutants (mre11delta, rad50delta, and spo11Y135F) defective for meiotic DSB formation, we demonstrate that the absence of Mre11 in yeast causes specific effects on regulation of a class of meiotic genes for spore development. The transcriptional deficiency was not observed in other DSB mutants such as rad50delta and spo11Y135F, suggesting the transcriptional defect in mre11delta is due to neither lack of meiotic DSB formation, nor disintegrity of Mre11-Rad50-Xrs2 complex.These defects were confirmed by northern and lacZ reporter gene assays. Experiment Overall Design: Gene expression data from wild type, mre11delta, rad50delta, and spo11Y135F cells in premeiosis (meiosis 0 hr) and prophase (meiosis 4 hr). Affymetrix GeneChip YG-S98 was used. All strains used were SK1 background diploid cells.
2007-10-23 | E-GEOD-6620 | biostudies-arrayexpress
Project description:To investigate the relationship between meiotic recombination initiation and H3K4m3 in Arabidopsis, we generated and sequenced H3K4m3 ChIP libraries from meiotic stage floral buds in wild type, arp6 and met1. To produce high-resolution of H3K4m3 mapping, we used micrococcal nuclease (MNase) to digest chromatins that were cross-linked by formaldehyde for ChIP. This experiment provides for H3K4m3 maps with the resolution of mononucleosomal DNA level (~150 bp).
2017-06-05 | E-MTAB-5048 | biostudies-arrayexpress
Project description:Meiotic recombination is initiated by the Spo11 endonuclease, which directs DNA DSBs. We report here that the recombinogenic cores of active hotspots in mice harbor several histone H3 and H4 acetylation and methylation marks that are typical of open, active chromatin. Further, deposition of these histone marks is dynamic and manifest at spermatogonia and/or pre-leptotene meiotic cells, which would facilitate the formation of DSBs at leptotene. Importantly, there was concordance in the overlap of the histone mark ChIP profiles with nucleosome occupancy maps, which were determined by real-time PCR and whole genome sequencing (WGS) analyses of micococcal-nuclease resistance regions across four mouse meiotic hotspots (HS22, HS59.4, HS59.5 and HS61.1). Our study reveals that there are instructive roles of histone acetylated marks at meiotic recombination hotspot cores and that they are necessary to promote hotspot activity and crossover resolution.
2016-11-04 | GSE87057 | GEO