A76a5f79-3bd6-40b2-bb41-cc34c18d6525 - samples
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PROVIDER: EGAD00001008756 | EGA |
REPOSITORIES: EGA
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Project description:We discovered two small molecule drugs - CX-5461 and CX-3543 - with specific toxicity against BRCA deficiencies in cancer cells and xenograft models. Both CX-5461 and CX-3543 have been previously recognized as RNA pol I inhibitors. CX-5461 is in advanced phase 1 trials for treatment of lymphoma and leukemia through rDNA transcription inhibition in a p53-dependent mechanism. We have discovered a novel activity of CX-5461, as a stabilizer of G-quadruplex DNA sequences inside cells the same as CX-3543. We found that BRCA1 and BRCA2 deficiency markedly increases (one log order) sensitivity to CX-5461 and a related drug CX-3543 in human cancer cell lines and polyclonal patient derived xenograft models, providing a direct therapeutic hypothesis, including PDX tumours resistant to PARP inhibition. We show that in epithelial cells, exposure to CX-5461 and CX-3543 blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543 induced DNA damage and failure to do so leads to lethality. RNA pol I inhibition is not a required component of the cell killing mechanism in these tumours, because BRCA2 deficient cells are not more sensitive to BMH-21, a more potent rDNA transcription inhibitor. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumors deficient for DNA damage repair. Since CX-5461 is already in advanced phase 1 trials for other indications, this has resulted in immediately testable translational implications (Canadian trial, NCT02719977, opened May 2016) as no phase-1 eligible G4 stabilizers have been described to date.
2016-12-06 | GSE90967 | GEO
Project description:DNA double strand breaks (DSBs) in B lymphocytes are thought to arise stochastically during replication (S phase) or as a result of targeted DNA damage by activation induced cytidine deaminase (AID) in G1. Here we identify a novel class of recurrent, early replicating and AID independent DNA lesions, termed early replication fragile sites (ERFS), by genome-wide localization of DNA repair proteins DNA double strand breaks (DSBs) in B lymphocytes are thought to arise stochastically during replication (S phase) or as a result of targeted DNA damage by activation induced cytidine deaminase (AID) in G1. Here we identify a novel class of recurrent, early replicating and AID independent DNA lesions, termed early replication fragile sites (ERFS), by genome-wide localization of DNA repair proteins DNA double strand breaks (DSBs) in B lymphocytes are thought to arise stochastically during replication (S phase) or as a result of targeted DNA damage by activation induced cytidine deaminase (AID) in G1. Here we identify a novel class of recurrent, early replicating and AID independent DNA lesions, termed early replication fragile sites (ERFS), by genome-wide localization of DNA repair proteins RPA, SMC5, gamma-H2AX, and BRCA1 in B cells subjected to replication stress.
2013-02-04 | GSE43504 | GEO
Project description:DNA double strand breaks (DSBs) in B lymphocytes are thought to arise stochastically during replication (S phase) or as a result of targeted DNA damage by activation induced cytidine deaminase (AID) in G1. Here we identify a novel class of recurrent, early replicating and AID independent DNA lesions, termed early replication fragile sites (ERFS), by genome-wide localization of DNA repair proteins DNA double strand breaks (DSBs) in B lymphocytes are thought to arise stochastically during replication (S phase) or as a result of targeted DNA damage by activation induced cytidine deaminase (AID) in G1. Here we identify a novel class of recurrent, early replicating and AID independent DNA lesions, termed early replication fragile sites (ERFS), by genome-wide localization of DNA repair proteins DNA double strand breaks (DSBs) in B lymphocytes are thought to arise stochastically during replication (S phase) or as a result of targeted DNA damage by activation induced cytidine deaminase (AID) in G1. Here we identify a novel class of recurrent, early replicating and AID independent DNA lesions, termed early replication fragile sites (ERFS), by genome-wide localization of DNA repair proteins RPA, SMC5, gamma-H2AX, and BRCA1 in B cells subjected to replication stress. Protein-DNA association for four DNA damage response proteins (RPA, SMC5, g-H2AX, BRCA1), BrdU incorporation, and gene transcription in B lymphocytes with and without hydroxyurea treatment were examined.
2013-02-04 | E-GEOD-43504 | biostudies-arrayexpress
Project description:Chromosome region maintenance protein1 (CRM1) mediates protein export from the nucleus and is a new target for anti-cancer therapeutics. Broader application of KPT-330 (Selinexor), a CRM1 inhibitor approved for myeloma, has been limited by toxicity. We found that combining choline salicylate (CS) with low-doses of KPT-330 (K+CS) had potent synergistic activity across blood and solid organ cancers ex-vivo and in-vivo. Mechanistically, K+CS enhances CRM1 degradation, induces potent inhibition of CRM1 mediated nuclear export, and arrests cells in S-phase with simultaneous reduction of Rad51 causing impaired DNA damage repair. K+CS represents a potential new class of therapy for multiple cancer types.
2020-10-28 | GSE160186 | GEO
Project description:Abstract Background: Histone deacetylase (HDAC) inhibition has shown some efficacy in urothelial carcinoma (UC); the genomic basis for clinical response is not known. Methods: In two separate phase I clinical trials testing HDAC inhibitors in advanced solid tumors, we identified one patient with advanced UC who had a complete response (CR) to belinostat and one with advanced UC who had a partial response (PR) to panobinostat. The archived tumor of the responders was genomically characterized and studied in comparison to others with UC, in the context of their response to HDAC inhibition on trial. UC cell lines treated with panobinostat were studied to elucidate the mechanisms of benefit. Results: The two patients who responded to HDAC inhibition had ARID1A and FANCD2 mutations. The patient who had a CR to HDAC inhibition had the highest tumor mutational burden of all tumors. Corroborating the basis of sensitivity, transcriptional profiling of platinum resistant ARID1A mutated HT1197 cells treated with panobinostat revealed downregulation of cyto-proliferative and DNA repair gene sets and upregulation of inflammatory gene sets. Conclusions: Clinical efficacy of HDAC inhibition in UC may be dependent on overlapping SWI/SNF pathway mutations and DNA repair defects. Tumor mutational burden may predict the depth and duration of benefit.
2018-10-31 | GSE103928 | GEO
Project description:Tumor specimen samples from the multi-site, international, phase I advanced solid tumor ETC-159 clinical trial (NCT02521844, A*STAR Research Entities, Singapore), were analyzed using the PanCancer IO panel
2021-02-19 | GSE167039 | GEO
Project description:Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons. The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is known about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here, we show that post-mitotic neurons accumulate unexpectedly high levels of DNA single-strand breakage at specific sites within the genome. Genome-wide mapping reveals that these single-strand breaks (SSBs) are located within enhancers at or near to CpG dinucleotides and sites of DNA demethylation, and are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair elevate the extent of DNA repair synthesis at neuronal enhancers, whereas deficiencies in long-patch repair reduce synthesis, suggesting that the high steady-state level of SSB repair in neuronal enhancers is sustained by both short-patch and long-patch processes. These data provide the first evidence of site- and cell type-specific SSB repair, revealing unexpected levels of localized and continuous DNA single-strand breakage in neurons. In addition, these data suggest an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.
2021-03-25 | GSE167258 | GEO
Project description:Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons. The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is known about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here, we show that post-mitotic neurons accumulate unexpectedly high levels of DNA single-strand breakage at specific sites within the genome. Genome-wide mapping reveals that these single-strand breaks (SSBs) are located within enhancers at or near to CpG dinucleotides and sites of DNA demethylation, and are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair elevate the extent of DNA repair synthesis at neuronal enhancers, whereas deficiencies in long-patch repair reduce synthesis, suggesting that the high steady-state level of SSB repair in neuronal enhancers is sustained by both short-patch and long-patch processes. These data provide the first evidence of site- and cell type-specific SSB repair, revealing unexpected levels of localized and continuous DNA single-strand breakage in neurons. In addition, these data suggest an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.
2021-03-25 | GSE167257 | GEO
Project description:Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons. The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is known about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here, we show that post-mitotic neurons accumulate unexpectedly high levels of DNA single-strand breakage at specific sites within the genome. Genome-wide mapping reveals that these single-strand breaks (SSBs) are located within enhancers at or near to CpG dinucleotides and sites of DNA demethylation, and are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair elevate the extent of DNA repair synthesis at neuronal enhancers, whereas deficiencies in long-patch repair reduce synthesis, suggesting that the high steady-state level of SSB repair in neuronal enhancers is sustained by both short-patch and long-patch processes. These data provide the first evidence of site- and cell type-specific SSB repair, revealing unexpected levels of localized and continuous DNA single-strand breakage in neurons. In addition, these data suggest an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.
2021-03-25 | GSE167256 | GEO
Project description:Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons. The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is known about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here, we show that post-mitotic neurons accumulate unexpectedly high levels of DNA single-strand breakage at specific sites within the genome. Genome-wide mapping reveals that these single-strand breaks (SSBs) are located within enhancers at or near to CpG dinucleotides and sites of DNA demethylation, and are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair elevate the extent of DNA repair synthesis at neuronal enhancers, whereas deficiencies in long-patch repair reduce synthesis, suggesting that the high steady-state level of SSB repair in neuronal enhancers is sustained by both short-patch and long-patch processes. These data provide the first evidence of site- and cell type-specific SSB repair, revealing unexpected levels of localized and continuous DNA single-strand breakage in neurons. In addition, these data suggest an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.
2021-03-25 | GSE167255 | GEO