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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45994 | GEO | 2013/09/01

SECONDARY ACCESSION(S): PRJNA196844

REPOSITORIES: GEO

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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

Homo sapiens

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

| PRJNA196844 | ENA

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

Proteomic profiling of interferon-responsive reactive astrocytes in rodent and human

Project description:Astrocytes are a heterogenous population of glial cells that respond to pathological insults or injury by undergoing a profound transformation called reactivity. Reactive astrocytes exhibit distinct, context-dependent cellular, molecular, and functional states that can either help or hinder tissue homeostasis. We recently identified a subtype of reactive astrocytes in the mouse brain called interferon-responsive reactive astrocytes (IRRAs), defined by interferon-responsive genes like Igtp, Ifit3, Oasl, Mx1, Cxcl10, and Gbp2 . To further this transcriptomic definition of IRRAs, we wanted to define the proteomic changes that occur in this sub-state.

2023-03-07 | MSV000091426 | MassIVE

Metabolic responses induced by DNA damage and poly (ADP-ribose) polymerase (PARP) inhibition in MCF-7 cells

Project description:Genomic instability is one of the hallmarks of cancer. Several chemotherapeutic drugs and radiotherapy induce DNA damage to prevent cancer cell replication. Cells in turn activate different DNA damage response (DDR) pathways to either repair the damage or induce cell death. These DDR pathways also elicit metabolic alterations which can play a significant role in the proper functioning of the cells. The understanding of these metabolic effects resulting from different types of DNA damage and repair mechanisms is currently lacking. In this study, we used NMR metabolomics to identify metabolic pathways which are altered in response to different DNA damaging agents. By comparing the metabolic responses in MCF-7 cells, we identified the activation of poly (ADP-ribose) polymerase (PARP) in methyl methanesulfonate (MMS)-induced DNA damage. PARP activation led to a significant depletion of NAD+. PARP inhibition using veliparib (ABT-888) was able to successfully restore the NAD+ levels in MMS-treated cells. In addition, double strand break induction by MMS and veliparib exhibited similar metabolic responses as zeocin, suggesting an application of metabolomics to classify the types of DNA damage responses. This prediction was validated by studying the metabolic responses elicited by radiation. Our findings indicate that cancer cell metabolic responses depend on the type of DNA damage responses and can also be used to classify the type of DNA damage.

2015-08-01 | MTBLS177 | MetaboLights

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

RecG Directs DNA Synthesis During Double-Strand Break Repair

Project description:RecG Directs DNA Synthesis During Double-Strand Break Repair

| PRJNA309667 | ENA

Proteomic alterations and novel markers of neurotoxic reactive astrocytes in human iPSC models

Project description:Astrocytes respond to injury, infection, and inflammation in the central nervous system by acquiring reactive states in which they may become dysfunctional and contribute to disease pathology. A sub-state of reactive astrocytes induced by proinflammatory factors TNF, IL-1a, and C1q (TIC) has been implicated in many neurodegenerative diseases as a source of neurotoxicity. Here, we used an established human induced pluripotent stem cell model to investigate the surface marker profile and proteome of TIC-induced reactive astrocytes. We propose VCAM1, BST2, ICOSL, HLA-E, PD-L1, and PDPN as putative, novel markers of this reactive sub-state. We found that several of these markers colocalize with GFAP-positive cells in post-mortem samples from people with Alzheimers disease. Moreover, our whole cell proteomic analysis of TIC-induced reactive astrocytes identified proteins and related pathways primarily linked to potential engagement with peripheral immune cells. Taken together, our findings will serve as new tools to purify reactive astrocyte subtypes and to further explore their involvement in immune responses associated with injury and disease.

2022-02-08 | MSV000088799 | MassIVE

Redox-Dependent Igfbp2 Signaling Controls Brca1 DNA Damage Response to Govern Neural Stem Cell Fate

Project description:Neural stem cell (NSC) maintenance and functions are regulated by reactive oxygen species (ROS). However, the mechanisms by which ROS control NSC behavior remain unclear. Here we report that ROS-dependent Igfbp2 signaling controls DNA repair pathways which balance NSC self-renewal and lineage commitment. Ncf1 or Igfbp2 deficiency constrained NSCs to a self-renewing state and prevented neurosphere formation due to absent Igfbp2 cysteine-43 oxidation. Ncf1-dependent oxidation of Igfbp2 promoted neurogenesis by NSCs in vitro and in vivo, while repressing Brca1 DNA damage response genes and inducing DNA double-strand breaks (DDSBs). By contrast, Ncf1–/– and Igfbp2–/– NSCs favored the formation of oligodendrocytes in vitro and in vivo. Notably, transient repression of Brca1 DNA repair pathway genes induced DDSBs and was sufficient to rescue the ability of Ncf1–/– and Igfbp2–/– NSCs to lineage-commit to form neurospheres and neurons. Our study highlights the role of DNA damage/repair in orchestrating NSC fate decisions downstream of redox-regulated Igfbp2.

2023-01-17 | GSE221955 | GEO

Project description:Repair-seq screens of double-strand break repair

| PRJNA746980 | ENA

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