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Genetic separation of Brca1 functions reveal mutation-dependent Pol theta vulnerabilities

ABSTRACT: We report DNA resection length after induced double stranded breaks in specific genomic loci with the expression of the AsisI restriction enzyme

ORGANISM(S): Mus musculus

PROVIDER: GSE244865 | GEO | 2023/11/29

REPOSITORIES: GEO

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BRCA1 mutational complementation induces synthetic viability

Project description:We report DNA resection length after induced double stranded breaks in specific genomic loci with the expression of the AsisI restriction enzyme

2020-03-24 | GSE147468 | GEO

Genetic separation of Brca1 functions reveal mutation-dependent Pol theta vulnerabilities

Project description:Genetic separation of Brca1 functions reveal mutation-dependent Pol theta vulnerabilities

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Genetic separation of Brca1 functions reveal mutation-dependent Polθ vulnerabilities.

Project description:Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq-/- cells were viable, but grew slowly and had chromosomal instability. Brca1 mutant cells proficient in DNA end resection were significantly more dependent on Polθ for viability; here, treatment with Polθi elevated RPA foci, which persisted through mitosis. In an isogenic system, BRCA1 null cells were defective, but PALB2 and BRCA2 mutant cells exhibited active resection, and consequently stronger sensitivity to Polθi. Thus, DNA end resection is a critical determinant of Polθi sensitivity in HR-deficient cells, and should be considered when selecting patients for clinical studies.

| S-EPMC10673838 | biostudies-literature

ChIP-Seq mapping of H2AK5ac, H2AK9ac, DNTTIP1, MIDEAS, and LIG4 at AsiSI-induced DNA double-strand breaks in control or MiDAC-deficient cells

Project description:To test whether MiDAC-promoted H2AK5/K9 deacetylation is implicated in DSB response, we took advantage of an improved DSB-induced via AsiSI (AiDIvA) system, in which the endonuclease restriction enzyme AsiSI is fused to the estrogen receptor (ER) hormone-binding domain and its nuclear expression in HeLa cells is controlled by doxycycline and 4-hydroxy tamoxifen (4-OHT). The precise distribution of gH2AX, H2AK5ac, H2AK9ac, FLAG-DNTTIP1, FLAG-MIDEAS, and LIG4 at AsiSI-induced DNA double-strand breaks was determined by chromatin immunoprecipitation coupled high throughput sequencing (ChIP-seq). ChIP signals from ER-AsiSI-expressing AiDIvA cells (DSB group) were normalized to ER-expressing control cells (Ctrl group).

2024-02-16 | GSE235845 | GEO

ChIP-seq mapping of gH2AX, PanKcr, H3K9cr, and ENL at AsiSI-induced double-strand breaks in control and CDYL1-depleted U2OS-DIvA cells

Project description:Control and CDYL1-depleted U2OS-DIvA cells were treated with 4-hydroxy tamoxifen (4OHT) to induce multiple DNA double-strand breaks (DSBs) at defined loci in the genome via AsiSI restriction enzyme. This system was used to map the changes in lysine crotonylation (Kcr) and ENL at DSB sites in control and CDYL1-deficient cells.

2022-01-22 | E-MTAB-10550 | biostudies-arrayexpress

Role of Polycomb group proteins in the DNA damage response – a reassessment

Project description:We have investigated whether components of Polycomb repressive complex 1 (PRC1) are recruited to double-strand breaks (DSBs) generated by inducible expression of the AsiSI restriction enzyme in normal human fibroblasts. Using chromatin immunoprecipitation and deep sequencing (ChIP-seq), which detects PRC1 proteins at common sites throughout the genome, we did not find evidence for recruitment of PRC1 components to AsiSI-induced DSBs. In contrast, the S2056 phosphorylated form of DNA-PKcs and other DNA repair proteins were detected at a subset of AsiSI sites that are predominantly at the 5’ ends of transcriptionally active genes. Our data question the idea that PcG protein recruitment provides a link between DSB repairs and transcriptional repression. Single chromatin preparations from treated and untreated cells (+/- OHT), immunoprecipitated with two antibodies (pDNA-PKcs and MEL18) were sequenced as technical replicates, along with the corresponding input DNAs

2014-07-06 | E-GEOD-55605 | biostudies-arrayexpress

Role of Polycomb group proteins in the DNA damage response – a reassessment

2014-07-06 | GSE55605 | GEO

Non redundant functions of ATM and DNAPKcs in response to clean DNA Double Strand Breaks.

Project description:DNA Double Strand Breaks (DSBs) are harmful lesions that require rapid detection and repair in order to avoid toxic genomic rearrangements. DSBs elicit the so called DNA Damage Response (DDR), largely relying on ataxia telangiectasia mutated (ATM) and DNA Protein Kinase (DNAPK), two members of the PI3K-like kinase family, whose respective functions during the sequential steps of the DDR remains controversial. Using the DIvA cell line, expressing the AsiSI restriction enzyme, we have investigated the role of ATM and DNAPK in several aspects of the DDR upon induction of multiple clean DSBs throughout the human genome. High resolution mapping revealed that they are activated and spread in cis on a confined region surrounding all DSBs, independently of the pathway used for repair. However, a thorough analysis of repair kinetics, H2AX domain establishment and H2AX foci structure and dynamics revealed non overlapping functions for the two kinases once recruited at DSBs. Our results suggest that ATM is not solely acting on chromatin marks but also on chromatin organisation in order to ensure repair accuracy and survival.

2015-09-30 | E-MTAB-2992 | biostudies-arrayexpress

DRIP-seq files for: DDX17 is required for efficient DSB repair at DNA:RNA hybrid deficient loci

Project description:Determining the role of DDX17 in the formation of DNA:RNA-hybrids around active DNA double-strand breaks (DSBs) using DRIP-seq in the damaged induced via AsiSI (DIvA) cell system that induced DSBs at known genomic loci in response to hydroxytamoxifen (OHT) treatment via and AsiSI enzyme fused to an oestrogen receptor. Sequencing was done using either control or DDX17 siRNA, and mock or 4 hours 300nM OHT treatment. Paired-end 150 cycles was completed on an Illumina NextSeq 500 and library prep was completed using the NEB NEBNext Ultra II library prep kit.

2022-11-08 | E-MTAB-10814 | biostudies-arrayexpress

Transcriptionally active chromatin channels DNA double-strand breaks to RAD51-dependent repair

Project description:Cells have developed effective mechanisms, namely homologous recombination (HR) and non-homologous end-joining (NHEJ), to repair DNA double-strand breaks (DSBs), which are considered to be the most deleterious type of damage that can challenge genome integrity. While these pathways coexist to repair DSBs, the mechanisms by which one of these pathways is chosen to repair a particular DSB remain unclear. Here, we show that the chromatin context in which a break occurs participates in this choice and that transcriptionnaly active chromatin channels repair to HR. By using a human cell line expressing a restriction enzyme fused to the ligand binding domain of the oestrogen receptor (AsiSI-ER)2,3, together with a genome wide chromatin immunoprecipitation-sequencing (ChIP-seq) approach, we establish that distinct DSBs induced across the genome are not necessarily repaired by the same pathway. Indeed, we identify an HR-prone subset of DSBs that recruit the HR protein RAD51, undergo resection, and rely on RAD51 for efficient repair. These DSBs are located in actively transcribed genes, and repair at such DSBs can be switched to RAD51-independent repair pathway upon transcriptional inhibition. Moreover, we show that HR is targeted to transcribed loci thanks to the elongation-associated H3K36me3 histone mark. Indeed depletion of HYPB, the main H3K36 tri methyltransferase severally impedes the use of HR at those DSBs. Our study, thereby demonstrates a clear role for chromatin in DSB repair pathway choice in human cells.

2014-03-23 | E-MTAB-1241 | biostudies-arrayexpress

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