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DNA damage repair in barley following double-strand breaks and its dependence on ATR

ABSTRACT: Maintaining genome integrity presents a particular challenge for plants due to their sedentary lifestyle, which disables direct avoidance of unfavorable external conditions. Additionally, plants’ metabolic processes generate reactive molecules as by-products of e.g. photosynthesis, creating internal DNA-damaging conditions. Due to this, plants have developed a unique and strictly regulated web of DNA damage responses (DDR). We initiated analysis of the DDR system in cultivated barley (Hordeum vulgare), a temperate cereal model with a large and repeat rich genome. A series of DNA damaging assays was established to describe barley plants’ phenotypic response to chemically induced DNA double-strand breaks. The efficacy of assays as a tool to be used for assessing potential new DDR barley mutants was demonstrated. DNA damage response network activation in barley was assessed by transcriptome analysis using RNA sequencing for wild type and mutant in the DDR signaling kinase ATAXIA TELANGIECTASIA MUTATED AND RAD3-RELATED (ATR). Considering the barley genome had only recently been sequenced, and it lacks the in-depth gene analysis, a list of potential DNA damage response genes in barley was compiled based on their homology with Arabidopsis genes. The comparison of transcripts in wild-type plants and atr mutants following genotoxic stress

ORGANISM(S): Hordeum vulgare

PROVIDER: GSE235051 | GEO | 2023/10/19

REPOSITORIES: GEO

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ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines

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2024-01-18 | GSE211272 | GEO

Transcription profiling of atm mutant, adm mutant and wild type whole plants and roots of Arabdiposis after gamma ray irradiation in a time series

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2006-10-30 | E-MEXP-780 | biostudies-arrayexpress

Downstream targets of ATR in CIN612 HPV-positive cells

Project description:High-risk human papillomaviruses (HPVs) constitutively activate the ataxia telangiectasia and Rad3-related (ATR) DNA damage response pathway for their replication. Although ATR has many reported functions, knowledge of how it regulates viral replication is limited. Most studies regarding ATR function focus on its roles in cell survival and initiation of DNA damage response. In this study, we examined whether the transcriptional regulatory properties directed by ATR are critical for HPV pathogenesis, and if so which downstream targets are important. Using RNA-seq approaches, we observed that ATR knockdown increases expression of many inflammatory genes. This mechanism is dependent on the p62/GATA4 signaling pathway.

2020-07-27 | GSE142482 | GEO

Genome-wide mapping of histone H2A phosphorylation during S-phase in Schizosaccharomyces pombe (fission yeast)

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Quantitative phosphoproteomics to unravel the cellular response to chemical stressors with different modes of action

Project description:Cells activate various stress response pathways when exposed to chemicals that can damage cellular macromolecules and organelles. Whether different chemical stressors activate common and/or stressor-specific pathways and to what extent is largely unclear. Here, we used quantitative phosphoproteomics to compare the phosphorylation signaling cascades induced by four stressors with different modes of action: the DNA damaging agent: cisplatin (CDDP), the topoisomerase II inhibitor: etoposide (ETO), the pro-oxidant: diethyl maleate (DEM) and the immunosuppressant: cyclosporine A (CsA). We show that equitoxic doses of these stressors induce distinctive and complex phosphorylation signaling cascades. Our results reveal stressor-specific kinase motifs and pathways. CDDP activates the DNA damage response (DDR) predominantly through the replication-stress related Atr kinase, whereas ETO triggers the DDR through Atr as well as the DNA double stranded break associated Atm kinase. CsA shares with ETO, a strong activation of CK2 kinase and significant Atm phosphorylation but lacks prominent activation of the DDR. Congruent with their known modes of action, CsA-mediated signaling is related to down-regulation of pathways that control hematopoietic differentiation and immunity whereas oxidative stress is the most prominent initiator of DEM-modulated stress signaling. This study presents an unprecedented molecular insight into the activated phosphorylation signaling cascades after various types of stressors.

2020-03-23 | PXD012559 | Pride

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

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2015-08-01 | MTBLS177 | MetaboLights

MET-dependent modulation of cellular responses to ionizing radiation by quantitative phosphoproteomics

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2020-05-15 | PXD009433 | Pride

Role of ATR in mitochondrial functions and metabolism

Project description:The PIKK superfamily member ATR is a key factor in DNA damage response (DDR) and is vital for the maintenance of genomic stability. DNA single strand breaks (SSBs) and replication stress activate ATR to phosphorylate a wide range of downstream substrates, which activates cell cycle checkpoint, senescence induction, cell death, and R-loop disintegration. ATR mutation causes the human ATR-Seckel syndrome, characterized by dwarfism, microcephaly and intellectual disabilities. Recent studies have implied ATR in non-nuclear functions; however, ATR's function in mitochondrial metabolism and a link to human diseases remains largely unknown. Here we show that ATR is located in mitochondria and its deletion alters mitochondrial dynamics prior to the DDR. ATR deletion disturbs the electron transfer chain (ETC) resulting in ROS overproduction and switches energy production from OXPHOS to the TCA cycle. Multi-omics analyses together with biochemical studies showed an imbalance of ETC proteins and membrane lipids accompanied with a dysregulation of key metabolic signaling pathways, including AMPK, mTOR and PGC1α. Pharmacological intervention of AMPK signaling or ETC functions delineates the metabolic pathways affected in ATR deleted cells. Mitochondrial metabolic dysfunction is more pronounced in ATR deleted neural cells and brain tissues, implicating a connection with neuropathological processes. Thus, ATR plays, beyond its well-known DDR function, an important role for cell metabolism and mitochondrial functionality, which contributes to the manifestation of neuronal deficit of ATR-Seckel.

2021-05-05 | PXD013414 | Pride

Phosphoproteomic profiling of the DNA damage response in MCF10A and human PBMC cells by SILAC labeling and 1D and 2D-LC-MS/MS

Project description:The DNA-damage response (DDR) is a critical network for maintaining genomic integrity, and mutations in the DDR are among the most frequently identified in tumors. Phosphorylation is a key signaling event in the DDR network. We sought to design high throughput, mass spectrometry based assays to monitor phosphopeptides in the DDR network for biological experiments and pharmacodynamics studies. These assays require an enrichment step, which can be done using antibodies. Developing antibodies de novo for phosphopeptide enrichment is costly and time-consuming, so we assessed the feasibility of immobilized-metal affinity chromatography (IMAC) enrichment coupled with multiple reaction monitoring-mass spectrometry (MRM-MS) for precise measurement of large numbers of phosphopeptides in the DDR network. Towards this goal, we evaluate the ability of the approach to reproducibly measure the endogenous phosphorylation levels of proteins associated with the DDR. Reproducibly detectable phosphopeptide targets for MRM-based assay development were empirically identified from LC-MS/MS analyses of SILAC-labeled MCF10A human breast epithelial cells exposed or mock-exposed to DNA damage. Samples were treated in triplicate with either ionizing radiation (IR) or methyl methanesulfonate (MMS) as the DNA-damaging agent. SILAC-labeled cells were prepared in two separate (label swap) experiments. First, treated cell lines were grown in heavy SILAC medium and untreated in light, and second, this labeling scheme was reversed. Untreated and treated cells were mixed at a 1:1 ratio by protein mass. To identify phosphopeptides at levels observable by MRM in an approach amenable to moderate throughput, a single step IMAC enrichment was developed for rapid processing of whole cell lysate.

2015-12-01 | PXD002363 | Pride

Expression data examining DNA damage responses in murine Abl Pre-B cells with genetic deficiencies in damage response genes

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2019-11-15 | GSE116388 | GEO

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