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DNA double-strand breaks induced by high NaCl occur predominantly in gene deserts

ABSTRACT: High concentration of NaCl increases DNA breaks both in cell culture and in vivo. The breaks remain elevated as long as NaCl concentration remains high and are rapidly repaired when the concentration is lowered. Repair of the breaks after NaCl is reduced is accompanied by formation of foci containing phosphorylated H2AX (γH2AX), which occurs around DNA double-strand breaks and contributes to their repair. By chromatin immunoprecipitation using anti-γH2AX antibody, followed by massive parallel sequencing (ChIP-Seq), we find that during repair of double–strand breaks induced by high NaCl, γH2AX is predominantly localized to regions of the genome devoid of genes (“gene deserts”), indicating that the high NaCl-induced double-strand breaks are located there. Localization to gene deserts helps explain why the DNA breaks are less harmful than are the random breaks induced by genotoxic agents such as UV radiation, ionizing radiation and oxidants. We propose that the universal presence of NaCl around animal cells has directly influenced the evolution of the structure of their genomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE32882 | GEO | 2011/11/21

SECONDARY ACCESSION(S): PRJNA146613

REPOSITORIES: GEO

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DNA double-strand breaks induced by high NaCl occur predominantly in gene deserts

Project description:High concentration of NaCl increases DNA breaks both in cell culture and in vivo. The breaks remain elevated as long as NaCl concentration remains high and are rapidly repaired when the concentration is lowered. Repair of the breaks after NaCl is reduced is accompanied by formation of foci containing phosphorylated H2AX (M-NM-3H2AX), which occurs around DNA double-strand breaks and contributes to their repair. By chromatin immunoprecipitation using anti-M-NM-3H2AX antibody, followed by massive parallel sequencing (ChIP-Seq), we find that during repair of doubleM-bM-^@M-^Sstrand breaks induced by high NaCl, M-NM-3H2AX is predominantly localized to regions of the genome devoid of genes (M-bM-^@M-^\gene desertsM-bM-^@M-^]), indicating that the high NaCl-induced double-strand breaks are located there. Localization to gene deserts helps explain why the DNA breaks are less harmful than are the random breaks induced by genotoxic agents such as UV radiation, ionizing radiation and oxidants. We propose that the universal presence of NaCl around animal cells has directly influenced the evolution of the structure of their genomes. ChIP-Seq experiment to find locations of M-NM-3H2AX in mouse genome

2011-11-21 | E-GEOD-32882 | biostudies-arrayexpress

Mus musculus

Project description:DNA double-strand breaks induced by high NaCl occur predominantly in gene deserts

| PRJNA146613 | ENA

DNA Double-Strand Breaks Induce H2Ax Phosphorylation Domains in a Contact-Dependent Manner

Project description:Efficient repair of DNA double-strand breaks (DSBs) requires a coordinated DNA Damage Response (DDR), which includes phosphorylation of histone H2Ax, forming γH2Ax. This histone modification spreads beyond the DSB into neighboring chromatin, generating a DDR platform that protects against end disassociation and degradation, minimizing chromosomal rearrangements. However, mechanisms that determine the breadth and intensity of γH2Ax domains remain unclear. Here, we show that chromosomal contacts of a DSB site are the primary determinants for γH2Ax landscapes. DSBs that disrupt a topological border permit extension of γH2Ax domains into both adjacent compartments. In contrast, DSBs near a border produce highly asymmetric DDR platforms, with γH2Ax nearly absent from one broken end. Collectively, our findings lend insights into a basic DNA repair mechanism and how the precise location of a DSB may influence genome integrity.

2020-05-13 | GSE150384 | GEO

MDC1 interacts with TOPBP1 to maintain chromosomal stability during mitosis

Project description:MDC1 is a large, modular phospho-protein scaffold that mediates recruitment of signaling and repair complexes to sites of DNA double-strand breaks (DSBs). MDC1 is anchored to damaged chromatin through interaction of its C-terminal BRCT-repeat domain with phosphorylated H2AX (γH2AX), where it recruits downstream factors via direct phosphorylation-dependent protein-protein interactions. Here, using unbiased proteomic analyses we identify a highly conserved protein interaction surface near the MDC1 N-terminus for the DNA damage response protein TOPBP1. We show that TOPBP1 directly binds to two residues in MDC1 that are phosphorylated by CK2. Interestingly, we find that TOPBP1 recruitment to DSBs depends on direct interaction with MDC1 only during mitosis. Furthermore, we demonstrate that disrupting MDC1-TOPBP1 binding causes hypersensitivity to ionizing radiation in mitosis, as well as increased micronuclei and chromosomal instability. Thus, our results highlight an important and hitherto unnoticed function for MDC1 and TOPBP1 in maintaining genome stability during cell division.

2019-03-25 | PXD011850 | Pride

RecG Directs DNA Synthesis During Double-Strand Break Repair [ChIP-seq]

Project description:In the bacterium Escherichia coli, RecG directs DNA synthesis during the repair of DNA double-strand breaks by homologous recombination. Examination of RecA binding during double-strand break repair in Escherichia coli in the presence and absence of RecG protein

2016-05-19 | E-GEOD-77181 | biostudies-arrayexpress

Transcription profiling of Saccharomyces cerevisiae treated with enediynes compared to gamma radiation

Project description:We are investigating the transcriptional response of yeast to treatment with enediynes or gamma radiation, which generate different extents of double or single strand breaks in DNA. We used microarrays to detail the global programme of gene expression underlying the DNA damage response in yeast Experiment Overall Design: Yeast were grown to mid log phase and treated with enediynes or gamma radiation (in biological triplicate) resulting in similar extents of cell killing. The responses were compared to each other and we have deciphered a gene expression profile that is specific for double and single strand breaks in DNA.

2009-04-23 | E-GEOD-5301 | biostudies-arrayexpress

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

Multi-Dimensional Epigenetic Analysis Reveals Transcription as a Primary Driver of Radiation Induced Double Strand Break Recognition

Project description:DNA Double Strand Breaks (DSBs) are a deleterious product of genotoxic agents or radiotherapy. Despite the inherent chromatin localization of DSBs, the literature has largely ignored the effect of local chromatin or histone post translational modifications (PTMs) on DSB induction or recognition especially in a therapy-relevant setting. Analysis of epigenetic linkages to the DNA Damage Response are challenging owing to the random nature of exogenous DSB induction. Here, we directly measure stochastic DNA damage induced by ionizing radiation (IR) and infer relationships between basal epigenetic states and cellular ability to detect DSBs. Contrary to the expected uniform localization of DSBs and γH2AX, we show that DSB recognition is separate from DSB induction and that both processes are dependent on the local chromatin milieu. In general, actively transcribed regions contain more γH2AX than heterochromatic regions suggesting a link between transcription and the DDR. In contrast to previous studies, we suggest that transcription proximal to DNA damage is necessary for early DSB detection and suggest a requirement for transcription mediated repair in genome maintenance. Finally, we reveal a dual effect of the repressive mark H3K27me3 on the DNA damage response. While basal H3K27me3 attenuates γH2AX deposition, transcribed regions recruit H3K27me3 following DSB induction possibly as an obligate step in DSB recognition. We uncover epigenetic determinants of DSB recognition and suggest new mechanisms by which the epigenome direct DNA repair. Our findings suggest new targets for radio-adjuvant therapy and reframe the current stochastic model of radiotherapy induced damage.

2021-12-31 | GSE181934 | GEO

Genome-wide Translocation Analysis in the 266Q Knock-in Mouse Model of SCA7

Project description:To determine whether a predisposition to DNA damage exists in SCA7 and how extensive the predilection to DNA damage might be in SCA7, we used LAM-HTGTS, a powerful high throughput next generation sequencing technique developed for monitoring of DNA double-strand break formation. We modified the LAM-HTGTS protocol by utilizing CRISPR-Cas9 to create the double-strand DNA break at a specific site and also added a step with a 5’ methyl cytosine modified primer to promote LpnPI endonuclease cleavage of sealed breaks to enrich for translocation events. Our unbiased native chromosome DNA repair experimentation revealed that expression of polyglutamine-expanded ataxin-7 yielded greatly reduced translocations in comparison to normal ataxin-7, which is consistent with retained canonical NHEJ repair, decreased HDR activity, and decreased SSA repair in SCA7 cells, as the classical NHEJ pathway is known to prevent translocation by ligating broken double-strand breaks.

2021-02-04 | GSE166119 | GEO

Cell transcriptional state alters genomic patterns of DNA double-strand break repair in human astrocytes

Project description:The misrepair of DNA double-strand breaks in close spatial proximity within the nucleus can result in chromosomal rearrangements that are important in the pathogenesis of hematopoietic and solid malignancies. It is unknown why certain epigenetic states, such as those found in stem or progenitor cells, appear to facilitate neoplastic transformation. Here we show that altering the transcriptional state of human astrocytes alters patterns of DNA damage repair from ionizing radiation at a gene locus-specific and genome-wide level. Astrocytes induced into a reactive state exhibited increased DNA repair, compared to non-reactive cells, in actively transcribed chromatin domains after irradiation. In mapping these sites of repair, we identified misrepair events and repair hotspots that were unique to each state. The precise characterization of genomic regions susceptible to mutation in specific epigenetic transcriptional states provides new opportunities for addressing clonal evolution in solid cancers, particularly those where double-strand break induction is a cornerstone of management. Primary astrocyte cells were cultured to confluency and went through a linear monolyer scratch or no scratch.

2013-09-01 | E-GEOD-45994 | biostudies-arrayexpress

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