scholarly journals Ataxia Telangiectasia Mutated (ATM)-mediated DNA Damage Response in Oxidative Stress-induced Vascular Endothelial Cell Senescence

2010 ◽  
Vol 285 (38) ◽  
pp. 29662-29670 ◽  
Author(s):  
Hong Zhan ◽  
Toru Suzuki ◽  
Kenichi Aizawa ◽  
Kiyoshi Miyagawa ◽  
Ryozo Nagai
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Endothelial Cell ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Vascular Endothelial Cell ◽  
Cell Senescence ◽  
Vascular Endothelial ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Response

scholarly journals Ataxia Telangiectasia Mutated Kinase Mediates NF-κB Serine 276 Phosphorylation and Interferon Expression via the IRF7-RIG-I Amplification Loop in Paramyxovirus Infection

2014 ◽  
Vol 89 (5) ◽  
pp. 2628-2642 ◽  
Author(s):  
Ling Fang ◽  
Sanjeev Choudhary ◽  
Bing Tian ◽  
Istvan Boldogh ◽  
Chunying Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Retinoic Acid ◽  
Dna Damage Response ◽  
Type I ◽  
Regulatory Factor ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Response ◽  
Amplification Loop ◽  
Inducible Gene

ABSTRACTRespiratory syncytial virus (RSV) is a primary etiological agent of childhood lower respiratory tract disease. Molecular patterns induced by active infection trigger a coordinated retinoic acid-inducible gene I (RIG-I)-Toll-like receptor (TLR) signaling response to induce inflammatory cytokines and antiviral mucosal interferons. Recently, we discovered a nuclear oxidative stress-sensitive pathway mediated by the DNA damage response protein, ataxia telangiectasia mutated (ATM), in cytokine-induced NF-κB/RelA Ser 276 phosphorylation. Here we observe that ATM silencing results in enhanced single-strand RNA (ssRNA) replication of RSVand Sendai virus, due to decreased expression and secretion of type I and III interferons (IFNs), despite maintenance of IFN regulatory factor 3 (IRF3)-dependent IFN-stimulated genes (ISGs). In addition to enhanced oxidative stress, RSV replication enhances foci of phosphorylated histone 2AX variant (γH2AX), Ser 1981 phosphorylation of ATM, and IKKγ/NEMO-dependent ATM nuclear export, indicating activation of the DNA damage response. ATM-deficient cells show defective RSV-induced mitogen and stress-activated kinase 1 (MSK-1) Ser 376 phosphorylation and reduced RelA Ser 276 phosphorylation, whose formation is required for IRF7 expression. We observe that RelA inducibly binds the native IFN regulatory factor 7 (IRF7) promoter in an ATM-dependent manner, and IRF7 inducibly binds to the endogenous retinoic acid-inducible gene I (RIG-I) promoter. Ectopic IRF7 expression restores RIG-I expression and type I/III IFN expression in ATM-silenced cells. We conclude that paramyxoviruses trigger the DNA damage response, a pathway required for MSK1 activation of phospho Ser 276 RelA formation to trigger the IRF7-RIG-I amplification loop necessary for mucosal IFN production. These data provide the molecular pathogenesis for defects in the cellular innate immunity of patients with homozygous ATM mutations.IMPORTANCERNA virus infections trigger cellular response pathways to limit spread to adjacent tissues. This “innate immune response” is mediated by germ line-encoded pattern recognition receptors that trigger activation of two, largely independent, intracellular NF-κB and IRF3 transcription factors. Downstream, expression of protective antiviral interferons is amplified by positive-feedback loops mediated by inducible interferon regulatory factors (IRFs) and retinoic acid inducible gene (RIG-I). Our results indicate that a nuclear oxidative stress- and DNA damage-sensing factor, ATM, is required to mediate a cross talk pathway between NF-κB and IRF7 through mediating phosphorylation of NF-κB. Our studies provide further information about the defects in cellular and innate immunity in patients with inherited ATM mutations.

scholarly journals INTS3 controls the hSSB1-mediated DNA damage response

2009 ◽  
Vol 187 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Jeffrey R. Skaar ◽  
Derek J. Richard ◽  
Anita Saraf ◽  
Alfredo Toschi ◽  
Emma Bolderson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Signaling Pathway ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Binding Protein ◽  
Ataxia Telangiectasia Mutated ◽  
Uncharacterized Protein ◽  
Damage Response ◽  
Atm Signaling Pathway ◽  
Atm Signaling

Human SSB1 (single-stranded binding protein 1 [hSSB1]) was recently identified as a part of the ataxia telangiectasia mutated (ATM) signaling pathway. To investigate hSSB1 function, we performed tandem affinity purifications of hSSB1 mutants mimicking the unphosphorylated and ATM-phosphorylated states. Both hSSB1 mutants copurified a subset of Integrator complex subunits and the uncharacterized protein LOC58493/c9orf80 (henceforth minute INTS3/hSSB-associated element [MISE]). The INTS3–MISE–hSSB1 complex plays a key role in ATM activation and RAD51 recruitment to DNA damage foci during the response to genotoxic stresses. These effects on the DNA damage response are caused by the control of hSSB1 transcription via INTS3, demonstrating a new network controlling hSSB1 function.

Sensitivity of tumor cells deficient in the fanconi anemia pathway to inhibition of ataxia telangiectasia mutated (ATM)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10509-10509
Author(s):  
R. D. Kennedy ◽  
P. Stuckert ◽  
E. Archila ◽  
M. De LaVega ◽  
C. Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Fanconi Anemia ◽  
Ataxia Telangiectasia ◽  
Pancreatic Head ◽  
Genotoxic Stress ◽  
Ataxia Telangiectasia Mutated ◽  
Chromosomal Breakage ◽  
Damage Response

10509 Loss of the fanconi anemia (FA) pathway function has been described in a number of sporadic tumor types including breast, ovarian, pancreatic, head and neck and hematological malignancies. Functionally, the FA pathway responds to stalled DNA replication following DNA damage. Given the importance of the FA pathway in the response to DNA damage, we hypothesized that cells deficient in this pathway may become hyper-dependent on alternative DNA damage response pathways in order to respond to endogenous genotoxic stress such as occurs during metabolism. Therefore, targeting these alternative pathways could offer therapeutic strategies in FA pathway deficient tumors. To identify new therapeutic targets we treated FA pathway competent and deficient cells with a DNA damage response siRNA library, that individually knocked out 230 genes. We identified a number of gene targets that were specifically toxic to FA pathway deficient cells, amongst which was the DNA damage response kinase Ataxia Telangiectasia Mutated (ATM). To test the requirement for ATM in FA pathway deficient cells, we interbred Fancg ± Atm± mice. Consistent with the siRNA screen result, Fancg-/- Atm-/- mice were non viable and Fancg± Atm-/- and Fancg-/- Atm ± progeny were less frequent that would have been expected. Several human cell lines with FA gene mutations were observed to have constitutive activation of ATM which was markedly reduced on correction with the appropriate wild-type FA gene. Interestingly, FA pathway deficient cells, including the FANCC mutant and FANCG mutant pancreatic cancer cell lines, were selectively sensitive to monotherapy with the ATM inhibitor KU55933, as measured by dose inhibition and colony count assays. FA pathway deficient cells also demonstrated an increased level of chromosomal breakage, cell cycle arrest and apoptosis following KU55933 treatment when compared to FA pathway corrected cells. We conclude that FA pathway deficient cells have an increased requirement for ATM activation in order to respond to sporadic DNA damage. This offers the possibility that monotherapy with ATM inhibitors could be a therapeutic strategy for tumors that are deficient for the FA pathway. No significant financial relationships to disclose.

scholarly journals Ataxia telangiectasia mutated- and Rad3-related kinase drives both the early and the late DNA-damage response to the monofunctional antitumour alkylator S23906

2011 ◽  
Vol 437 (1) ◽  
pp. 63-73 ◽  
Author(s):  
Daniele G. Soares ◽  
Aude Battistella ◽  
Céline J. Rocca ◽  
Renata Matuo ◽  
João A. P. Henriques ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Anticancer Agents ◽  
Ataxia Telangiectasia ◽  
Kinase Inhibitors ◽  
Protein A ◽  
Initial Response ◽  
Synergistic Activity ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Response

Numerous anticancer agents and environmental mutagens target DNA. Although all such compounds interfere with the progression of the replication fork and inhibit DNA synthesis, there are marked differences in the DNA-damage response pathways they trigger, and the relative impact of the proximal or the distal signal transducers on cell survival is mainly lesion-specific. Accordingly, checkpoint kinase inhibitors in current clinical development show synergistic activity with some DNA-targeting agents, but not with others. In the present study, we characterize the DNA-damage response to the antitumour acronycine derivative S23906, which forms monofunctional adducts with guanine residues in the minor groove of DNA. S23906 exposure is accompanied by specific recruitment of RPA (replication protein A) at replication sites and rapid Chk1 activation. In contrast, neither MRN (Mre11-Rad50-Nbs1) nor ATM (ataxia-telangiectasia mutated), contributes to the initial response to S23906. Interestingly, genetic attenuation of ATR (ATM- and Ras3-related) activity inhibits not only the early phosphorylation of histone H2AX and Chk1, but also interferes with the late phosphorylation of Chk2. Moreover, loss of ATR function or pharmacological inhibition of the checkpoint kinases by AZD7762 is accompanied by abrogation of the S-phase arrest and increased sensitivity towards S23906. These findings identify ATR as a central co-ordinator of the DNA-damage response to S23906, and provide a mechanistic rationale for combinations of S23906 and similar agents with checkpoint abrogators.

Sign in / Sign up

Export Citation Format

Share Document