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ATM regulates a DNA damage response post-transcriptional RNA operon in lymphocytes

ABSTRACT: Maintenance of genomic stability depends on the DNA damage response (DDR), a biological barrier in early stages of cancer development. Failure of this response results in genomic instability and high predisposition toward lymphoma, as seen in patients with ataxia-telangiectasia mutated (ATM) dysfunction. ATM activates multiple cell cycle checkpoints and DNA repair following DNA damage, but its influence on posttranscriptional gene expression has not been examined on a global level. We show that ionizing radiation (IR) modulates the dynamic association of the RNA-binding protein HuR with target mRNAs in an ATM-dependent manner, potentially coordinating the genotoxic response as an RNA operon. Pharmacologic ATM inhibition and use of ATM-null cells revealed a critical role for ATM in this process. Numerous mRNAs encoding cancer-related proteins were differentially associated with HuR depending on the functional state of ATM, in turn affecting expression of encoded proteins. The findings presented here reveal a previously unidentified role of ATM in controlling gene expression post-transcriptionally. Dysregulation of this DDR RNA operon is likely relevant to lymphoma development in ataxia-telangiectasia individuals. These novel RNA regulatory modules and genetic networks provide critical insight into the function of ATM in oncogenesis. B-lymphocyte cell lines GM02184 (wild type, ATM +/+) and GM03332 (AT, ATM -/-) were either untreated or exposed to 1 Gy of IR. 6 h later cells were harvested and used for immunoprecipitation (IP) in the presence of HuR antibody (Santa Cruz Biotech.). RNA from IP material was extracted and used for microarray analysis.

ORGANISM(S): Homo sapiens

SUBMITTER: Kevin Becker

PROVIDER: E-GEOD-25848 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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ATM regulates a DNA damage response post-transcriptional RNA operon in lymphocytes

Project description:Maintenance of genomic stability depends on the DNA damage response (DDR), a biological barrier in early stages of cancer development. Failure of this response results in genomic instability and high predisposition toward lymphoma, as seen in patients with ataxia-telangiectasia mutated (ATM) dysfunction. ATM activates multiple cell cycle checkpoints and DNA repair following DNA damage, but its influence on posttranscriptional gene expression has not been examined on a global level. We show that ionizing radiation (IR) modulates the dynamic association of the RNA-binding protein HuR with target mRNAs in an ATM-dependent manner, potentially coordinating the genotoxic response as an RNA operon. Pharmacologic ATM inhibition and use of ATM-null cells revealed a critical role for ATM in this process. Numerous mRNAs encoding cancer-related proteins were differentially associated with HuR depending on the functional state of ATM, in turn affecting expression of encoded proteins. The findings presented here reveal a previously unidentified role of ATM in controlling gene expression post-transcriptionally. Dysregulation of this DDR RNA operon is likely relevant to lymphoma development in ataxia-telangiectasia individuals. These novel RNA regulatory modules and genetic networks provide critical insight into the function of ATM in oncogenesis.

2011-01-05 | GSE25848 | GEO

Transcription profiling of ATM +/+, ATM +/- and ATM -/- human lymphoblastoid cell lines exposed to 5 Gy IR at 0, 4 and 24 hours to identify expression phenotypes in Ataxia Telangiectasia carriers and patients

Project description:Transcription profiling of ATM (Ataxia Telangiectasia Mutated) +/+ (Control), ATM +/- (AT Carrier) and ATM -/- (AT patient) human lymphoblastoid cell lines exposed to 5 Gy IR at 0, 4 and 24 hours to identify expression phenotypes in Ataxia Telangiectasia carriers and patients

2008-07-29 | E-TABM-321 | biostudies-arrayexpress

Gene expressioin signatures in human lymphoblastoid cell lines with different ataxia telangiectasia-mutated (ATM) genotypes post sham- or IR-treatment

Project description:Transcriptional profiling of human lymphoblastoid cell lines with different ATM genotypes 6h post sham- or 1.5 Gy IR-treatmentl was compared to extract IR-related gene expression signatures that can identify ataxia telangiectasia (AT) carries from non AT carries and AT patients.

2013-04-09 | GSE45849 | GEO

Gene expressioin signatures in human lymphoblastoid cell lines with different ataxia telangiectasia-mutated (ATM) genotypes post sham- or IR-treatment

2013-04-09 | E-GEOD-45849 | biostudies-arrayexpress

Influence of ATM-mediated DNA damage response on genomic variation in human induced pluripotent stem cells (Affymetrix expression)

Project description:Genome instability is a potential limitation to the research and therapeutic application of induced pluripotent stem cells (iPSCs). Observed genomic variations reflect the combined activities of DNA damage, cellular DNA damage response (DDR), and selection pressure in culture. To understand the contribution of DDR on the distribution of copy number variations (CNVs) in iPSCs, we mapped CNVs of iPSCs with mutations in the central DDR gene ATM onto genome organization landscapes defined by genome-wide replication timing profiles. We show that following reprogramming the early and late replicating genome is differentially affected by CNVs in ATM deficient iPSCs relative to wild type iPSCs. Specifically, the early replicating regions had increased CNV losses during retroviral reprogramming. This differential CNV distribution was not present after later passage or after episomal reprogramming. Comparison of different reprogramming methods in the setting of defective DNA damage response reveals unique vulnerability of early replicating open chromatin to retroviral vectors. We isolated RNA from Ataxia-telangiectasia (A-T) patient fibroblast derived iPS cells and A-T patient fibroblasts for hybridization to the Affymetrix gene expression microarrays.

2016-03-29 | E-GEOD-78716 | 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

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

ATM Requirement in Gene Expression Responses to Ionizing Radiation in Human Lymphoblasts and Fibroblasts

Project description:Investigation of ATM-dependent and dose-dependent, or -independent, responses were examined in human lymphoblast cells 6 hr following exposure to either 1 or 5 Gy ionizing radiation. Human lymphoblast cells from "apparently healthy" individuals and individuals with Ataxia telangiectasia were exposed to 1 Gy or 5 Gy ionizing radiation. Gene expression responses 6 hr following IR were examined. Untreated samples were hybridized together with their matched treated samples.

2010-07-01 | E-GEOD-3174 | biostudies-arrayexpress

Tunable regulation of CREB DNA binding activity couples genotoxic stress response and metabolism

Project description:In this study we show that, in embryonic fibroblasts from mice on a high fat diet and treated with Forskolin, ionizing radiation exposure or both, phosphorylation of CREB-binding protein (CREB) by ATM (ataxia-telangiectasia-mutated) and casein kinases 1 and 2 (CK1 and CK2) on a cluster of five phosphorylation sites (the ATM/CK cluster) within the unstructured kinase-inducible domain (KID) provides an additional level of regulation through dynamic modulation of CREB DNA binding activity. Stoichiometric phosphorylation of the ATM/CK cluster in response to DNA damage inhibited cAMP-induced CREB target gene expression, CREB DNA binding activity, and CREB-CRTC2-DNA ternary complex formation proportional to the number of phosphate residues modified. Substoichiometric phosphorylation of the ATM/CK cluster promoted cAMP/Ca2+-regulated transcriptional coactivators (CRTCs) recruitment and CREB activation via an ATM-independent, PKA-dependent pathway. Mice expressing a non-phosphorylatable CREBS111A allele exhibited phenotypes consistent with CREB deregulation, including fasting hyperglycemia, susceptibility to diet-induced obesity, and reduced expression of gluconeogenic genes. Two genotypes: CREB+/+ (wild type) and CREBS111A (non-phosphorylatable CREB KID S111A mutant allele) each control treated, exposed to forskolin, ionizing radiation or both in triplicate and in two batches toataling 48 arrays

2016-07-01 | E-GEOD-83891 | biostudies-arrayexpress

ATM-knockout on total and phosphorylation proteomes of cortical brain organoids

Project description:ATM (ataxia telangiectasia mutated) kinase is crucial to a wide range of human developmental disorders and adult/pediatric malignancies. Its mutations are causally tied to ataxia telangiectasia, a multi-systemic congenital disorder mainly affecting brain and blood systems. We generated 4 separate ATM-knockout human pluripotent stem cell lines and differentiated them to form 3-dimensional brain cortical brain organoids. Brain cortical organoids are an excellent model of human developing cortex. Using these analyses, we identified ATM-dependent phosphorylation predominantly influences factors in neurogenesis, neuronal differentiation, cell morphogenesis, and microtubule cytoskeleton as well as kinases involved in ATM, BNDF, and WNT signaling, G2/M checkpoint, and p53 regulation. These findings have broad implications about diseases associated with ATM, including ataxia telangiectasia.

2024-07-25 | PXD041699 | Pride

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