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Cancer Cell Resistance to IFNγ Can Occur via Enhanced Double-Strand Break Repair Pathway Activity [CRISPR screen]

ABSTRACT: The pleiotropic cytokine interferon-gamma (IFNγ) is known to be associated with cytostatic, anti-proliferation, and pro-apoptosis functions in cancer cells. However, cancer cells can become resistant to IFNγ, and the underlying mechanism is not fully understood. To investigate the potential IFNγ resistant mechanisms, we performed IFNγ sensitivity screens in more than 40 cancer cell lines and characterized the sensitive and resistant cell lines. By applying CRISPR screening and transcriptomic profiling in both IFNγ sensitive and resistant cells, we discovered that activation of double-strand break (DSB) repair genes could result in IFNγ resistance in cancer cells. In addition, suppression of single-strand break (SSB) repair genes increased the essentiality of DSB repair genes after IFNγ treatment. The relationship between the activation of DSB repair genes and IFNγ resistance was further confirmed in clinical tumor profiles from The Cancer Genome Atlas (TCGA) and immune checkpoint blockade (ICB) cohorts. Our study provides a comprehensive resource to elucidate IFNγ resistance in cancer and has the potential to inform combinational therapeutic strategies to overcome immunotherapy resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180942 | GEO | 2023/02/28

REPOSITORIES: GEO

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Cancer Cell Resistance to IFNγ Can Occur via Enhanced Double-Strand Break Repair Pathway Activity [RNA-seq]

Project description:The pleiotropic cytokine interferon-gamma (IFNγ) is known to be associated with cytostatic, anti-proliferation, and pro-apoptosis functions in cancer cells. However, cancer cells can become resistant to IFNγ, and the underlying mechanism is not fully understood. To investigate the potential IFNγ resistant mechanisms, we performed IFNγ sensitivity screens in more than 40 cancer cell lines and characterized the sensitive and resistant cell lines. By applying CRISPR screening and transcriptomic profiling in both IFNγ sensitive and resistant cells, we discovered that activation of double-strand break (DSB) repair genes could result in IFNγ resistance in cancer cells. In addition, suppression of single-strand break (SSB) repair genes increased the essentiality of DSB repair genes after IFNγ treatment. The relationship between the activation of DSB repair genes and IFNγ resistance was further confirmed in clinical tumor profiles from The Cancer Genome Atlas (TCGA) and immune checkpoint blockade (ICB) cohorts. Our study provides a comprehensive resource to elucidate IFNγ resistance in cancer and has the potential to inform combinational therapeutic strategies to overcome immunotherapy resistance.

2023-02-28 | GSE180941 | GEO

Ma2005-digital response of p53 to DNA damage-ATM Activation Module

Project description:Recent observations show that the single-cell response of p53 to ionizing radiation (IR) is “digital” in that it is the number of oscillations rather than the amplitude of p53 that shows dependence on the radiation dose. We present a model of this phenomenon. In our model, double-strand break (DSB) sites induced by IR interact with a limiting pool of DNA repair proteins, forming DSB–protein complexes at DNA damage foci. The persisting complexes are sensed by ataxia telangiectasia mutated (ATM), a protein kinase that activates p53 once it is phosphorylated by DNA damage. The ATM-sensing module switches on or off the downstream p53 oscillator, consisting of a feedback loop formed by p53 and its negative regulator, Mdm2. In agreement with experiments, our simulations show that by assuming stochasticity in the initial number of DSBs and the DNA repair process, p53 and Mdm2 exhibit a coordinated oscillatory dynamics upon IR stimulation in single cells, with a stochastic number of oscillations whose mean increases with IR dose. The damped oscillations previously observed in cell populations can be explained as the aggregate behavior of single cell

2020-05-13 | MODEL2005130001 | BioModels

Quantitative Genomic Analysis of RecA Protein Binding During DNA Double-Strand Break Repair Reveals RecBCD Action in vivo

Project description:Here we have developed a method that combines chromatin immunoprecipitation with next-generation sequencing (ChIP-Seq) and mathematical modeling to quantify RecA protein binding during the active repair of a single DSB in the chromosome of Escherichia coli. Examination of RecA binding during double-strand break repair in Escherichia coli

2015-08-11 | E-GEOD-71249 | biostudies-arrayexpress

A Role for Small RNAs in DNA Double-Strand Break Repair

Project description:Here we identify a novel class of small RNAs that are ~21-nucleotide in length and are produced from the sequences in the vicinity of DNA double strand break (DSB) sites in Arabidopsis and humans. We named them diRNAs for DSB-induced small RNAs. In Arabidopsis, the biogenesis of diRNAs requires the PI3 kinase ATR, RNA polymerase IV (Pol IV), and Dicer-like proteins. Mutations in these proteins as well as in Pol V cause significant reduction in DSB repair efficiency. diRNAs are recruited by Argonaute 2 (AGO2) to mediate DSB repair. In humans, knocking down Dicer or Ago2 causes a significant reduction in DSB repair. Our findings reveal a novel biological function for small RNAs in the DSB repair pathway. We propose that diRNAs may function as guide molecules for chromatin modifications or recruitment of repair complexes at DSB sites to facilitate repair. 28 samples from Arabidopsis thaliana in various genetic backgrounds and 5 samples from the human cells, small RNA sequencing

2012-03-26 | E-GEOD-36338 | biostudies-arrayexpress

RAD54L2 mediates a novel mechanism to counter TOP2-DNA adducts

Project description:The catalytic cycle of topoisomerase 2 (TOP2) enzymes proceeds via a transient DNA double-strand break (DSB) intermediate termed the TOP2 cleavage complex (TOP2cc), in which the TOP2 protein is covalently bound to DNA. Anti-cancer agents such as etoposide operate by stabilising TOP2ccs, ultimately generating genotoxic TOP2-DNA protein crosslinks that require processing and repair. Here, we identify RAD54L2 as a factor promoting TOP2cc resolution. We demonstrate that RAD54L2 acts through a novel mechanism together with ZNF451 and independent of TDP2. Our work suggests a model wherein RAD54L2 recognises sumoylated-TOP2 and, using its ATPase activity, promotes TOP2cc resolution and prevents DSB exposure. These findings suggest RAD54L2-mediated TOP2cc resolution as a potential mechanism for cancer-therapy resistance and highlight RAD54L2 as an attractive candidate for drug discovery.

2024-01-26 | PXD046611 | Pride

Transcriptional effects of I-PpoI induced DNA double strand breaks in mouse lymphocytes

Project description:DNA double-strand breaks (DSBs) and their repair can cause extensive epigenetic changes. As a result, DSBs have been proposed to promote transcriptional and, ultimately, physiological dysfunction via both cell-intrinsic and cell-non-autonomous pathways. Studying the consequences of DSBs in higher organisms has, however, been hindered by a scarcity of tools for controlled DSB induction. Using a mouse model for both tissue-specific and temporally controlled DSB formation, we investigated the transcriptional response to break repair. Transcriptional profiling of lymphocytes in spleen and thymus by RNA-Seq, with and without I-PpoI knock-in.

2016-01-04 | E-GEOD-74855 | biostudies-arrayexpress

ATM-ESCO2-SMC3 axis regulates cohesin-dependent chromatin structure dynamics in response to DNA damage and safeguards genome integrity by promoting 53BP1 recruitment

Project description:53BP1 is primarily known as a key regulator in DNA double-strand break (DSB) repair. However, the mechanism of DSB-triggered cohesin modification-modulated chromatin structure on the recruitment of 53BP1 remains largely elusive. Here we identified acetyltransferase ESCO2 as a regulator for DSB-induced cohesin-dependent chromatin structure dynamics, which promotes 53BP1 recruitment. Mechanistically, in response to DNA damage, ATM phosphorylates ESCO2 S196 and T233. MDC1 recognizes phosphorylated ESCO2 and recruits ESCO2 to DSB sites. ESCO2-mediated acetylation of SMC3 stabilizes cohesin complex conformation and regulates the chromatin structure at DSB breaks, which is essential for the recruitment of 53BP1 and the formation of 53BP1 microdomains. Furthermore, depletion of ESCO2 in both colorectal cancer cells and xenografted nude mice sensitizes cancer cells to chemotherapeutic drugs. Collectively, our results reveal a molecular mechanism for the ATM-ESCO2-SMC3 axis in DSB repair and genome integrity maintenance with a vital role in chemotherapy response in colorectal cancer.

2023-12-16 | GSE221266 | GEO

Comparative proteomic analysis identifies differentially expressed proteins associated with meiotic arrest in cattle-yak hybrids

Project description:Comparative proteomic analysis identified a total of 452 differentially abundant proteins (DAPs) in the fluorescence-activated cell sorting (FACS) isolated spermatocytes from 12-month-old yak and cattleyak. 291 proteins were only identified in yak spermatocytes. Gene Ontology analysis revealed that the downregulated DAPs were mostly enriched in the cellular response to DNA damage stimulus and double-strand break (DSB) repair via break-induced replication, while the proteins specific for yak were related to cell division and cycle, spermatogenesis, and negative regulation of the extrinsic apoptotic signaling pathway.

2023-03-21 | PXD043039 | iProX

A Role for Small RNAs in DNA Double-Strand Break Repair

2012-03-27 | GSE36338 | GEO

DNA methylation is stable after MMEJ and NHEJ double strand break repair

Project description:DNA double strand breaks (DSBs) are a major source of mutations. Both non-homologous-end-joining (NHEJ) and microhomology-mediated-end-joining (MMEJ) DSB repair pathways are error prone and produce deletions, which can lead to cancer. DSBs also lead to epigenetic changes, including demethylation, which is involved in carcinogenesis. Of specific interest is the MMEJ repair pathway, as it requires methylation restoration around the break, as a result of the resection and formation of single stranded (ssDNA) intermediates. While, methylation patterns after homologous recombination (HR) have been partially studied, the methylation status after MMEJ and NHEJ remains poorly reported, and can be relevant for cancer. To study methylation patterns around DSB after NHEJ and MMEJ repair, we used targeted bisulfite-sequencing (BS-seq) to quantify methylation of dozens of single cell clones after induction of DSB by CRISPR. Each single cell clone was classified according to the sequence signature to a specific repair mechanism: NHEJ or MMEJ. Comparison of single cell clones after DSB to control cells, without DSB, demonstrated correct restoration of the methylation levels. No difference in methylation patterns was noticed when comparing NHEJ to MMEJ. Methylation levels in gene body, highly methylated CpGs (n=61, 4000 base pairs around DSB) and in low methylation CpGs (n=19), remained stable after both MMEJ and NHEJ. Gene body methylation persisted even on the background of DNMT3A R882C mutation, the most prevalent preleukemic mutation, in which the de novo methylation machinery is compromised. An exception observed in a single CpG site (ASXL1 995) which demonstrated elevated methylation rate after DSB repair only in the presence of WT DNMT3A. In summary, DNA methylation restoration demonstrated high fidelity after DSB both in methylated and unmethylated gene body, even in cases where DNA resections and deletions occurred.

2022-09-11 | E-MTAB-12037 | biostudies-arrayexpress

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