Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 330 (6003): 517-521

Copyright © 2010 by the American Association for the Advancement of Science

ATM Activation by Oxidative Stress

Zhi Guo,1 Sergei Kozlov,2 Martin F. Lavin,2 Maria D. Person,3 Tanya T. Paull1,*

Abstract: The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide–cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.

1 Howard Hughes Medical Institute, Department of Molecular Genetics and Microbiology, and Institute for Cellular and Molecular Biology (ICMB), University of Texas at Austin, Austin, TX 78712, USA.
2 Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, and School of Medicine, University of Queensland, Brisbane Q4006, Australia.
3 ICMB Analytical Instrumentation Facility Core, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA.

* To whom correspondence should be addressed. E-mail: tpaull{at}mail.utexas.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A patient-derived olfactory stem cell disease model for ataxia-telangiectasia.
R. Stewart, S. Kozlov, N. Matigian, G. Wali, M. Gatei, R. Sutharsan, B. Bellette, A. Wraith-Kijas, J. Cochrane, M. Coulthard, et al. (2013)
Hum. Mol. Genet. 22, 2495-2509
   Abstract »    Full Text »    PDF »
Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions.
M. Ambrose and R. A. Gatti (2013)
Blood 121, 4036-4045
   Abstract »    Full Text »    PDF »
Ataxia Telangiectasia-Mutated (ATM) Kinase Activity Is Regulated by ATP-driven Conformational Changes in the Mre11/Rad50/Nbs1 (MRN) Complex.
J.-H. Lee, M. R. Mand, R. A. Deshpande, E. Kinoshita, S.-H. Yang, C. Wyman, and T. T. Paull (2013)
J. Biol. Chem. 288, 12840-12851
   Abstract »    Full Text »    PDF »
The Ataxia Telangiectasia Mutated Kinase Pathway Regulates IL-23 Expression by Human Dendritic Cells.
Q. Wang, H. A. Franks, S. J. Lax, M. El Refaee, A. Malecka, S. Shah, I. Spendlove, M. J. Gough, C. Seedhouse, S. Madhusudan, et al. (2013)
J. Immunol. 190, 3246-3255
   Abstract »    Full Text »    PDF »
G-protein Inactivator RGS6 Mediates Myocardial Cell Apoptosis and Cardiomyopathy Caused By Doxorubicin.
J. Yang, B. Maity, J. Huang, Z. Gao, A. Stewart, R. M. Weiss, M. E. Anderson, and R. A. Fisher (2013)
Cancer Res. 73, 1662-1667
   Abstract »    Full Text »    PDF »
DNA damage-independent apoptosis induced by curcumin in normal resting human T cells and leukaemic Jurkat cells.
Z. Korwek, A. Bielak-Zmijewska, G. Mosieniak, O. Alster, M. Moreno-Villanueva, A. Burkle, and E. Sikora (2013)
Mutagenesis
   Abstract »    Full Text »    PDF »
Brain and induced pluripotent stem cell-derived neural stem cells as an in vitro model of neurodegeneration in ataxia-telangiectasia.
L. Carlessi, E. F. Poli, and D. Delia (2013)
Exp Biol Med 238, 301-307
   Abstract »    Full Text »    PDF »
DNA damage response in monozygotic twins discordant for smoking habits.
F. Marcon, D. Carotti, C. Andreoli, E. Siniscalchi, P. Leopardi, S. Caiola, M. Biffoni, A. Zijno, E. Medda, L. Nistico, et al. (2013)
Mutagenesis 28, 135-144
   Abstract »    Full Text »    PDF »
DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking.
T. Kondo, J. Kobayashi, T. Saitoh, K. Maruyama, K. J. Ishii, G. N. Barber, K. Komatsu, S. Akira, and T. Kawai (2013)
PNAS 110, 2969-2974
   Abstract »    Full Text »    PDF »
Cell cycle stage-specific roles of Rad18 in tolerance and repair of oxidative DNA damage.
Y. Yang, M. Durando, S. L. Smith-Roe, C. Sproul, A. M. Greenwalt, W. Kaufmann, S. Oh, E. A. Hendrickson, and C. Vaziri (2013)
Nucleic Acids Res. 41, 2296-2312
   Abstract »    Full Text »    PDF »
Movement Disorder in Ataxia-Telangiectasia: Treatment With Amantadine Sulfate.
A. Nissenkorn, S. Hassin-Baer, S. F. Lerman, Y. B. Levi, M. Tzadok, and B. Ben-Zeev (2013)
J Child Neurol 28, 155-160
   Abstract »    Full Text »    PDF »
Ataxia telangiectasia mutated impacts insulin-like growth factor 1 signalling in skeletal muscle.
J. K. Ching, S. H. Luebbert, R. L. Collins IV, Z. Zhang, N. Marupudi, S. Banerjee, R. D. Hurd, L. Ralston, and J. S. Fisher (2013)
Exp Physiol 98, 526-535
   Abstract »    Full Text »    PDF »
ISG15 Deregulates Autophagy in Genotoxin-treated Ataxia Telangiectasia Cells.
S. D. Desai, R. E. Reed, S. Babu, and E. A. Lorio (2013)
J. Biol. Chem. 288, 2388-2402
   Abstract »    Full Text »    PDF »
The Cellular Ataxia Telangiectasia-Mutated Kinase Promotes Epstein-Barr Virus Lytic Reactivation in Response to Multiple Different Types of Lytic Reactivation-Inducing Stimuli.
S. R. Hagemeier, E. A. Barlow, Q. Meng, and S. C. Kenney (2012)
J. Virol. 86, 13360-13370
   Abstract »    Full Text »    PDF »
Heat induction of a novel Rad9 variant from a cryptic translation initiation site reduces mitotic commitment.
S. Janes, U. Schmidt, K. Ashour Garrido, N. Ney, S. Concilio, M. Zekri, and T. Caspari (2012)
J. Cell Sci. 125, 4487-4497
   Abstract »    Full Text »    PDF »
The ATM protein: The importance of being active.
Y. Shiloh and Y. Ziv (2012)
J. Cell Biol. 198, 273-275
   Abstract »    Full Text »    PDF »
Development of a High-Content High-Throughput Screening Assay for the Discovery of ATM Signaling Inhibitors.
C. Bardelle and J. Boros (2012)
J Biomol Screen 17, 912-920
   Abstract »    Full Text »    PDF »
A p53 Axis Regulates B Cell Receptor-Triggered, Innate Immune System-Driven B Cell Clonal Expansion.
H. Lee, S. Haque, J. Nieto, J. Trott, J. K. Inman, S. McCormick, N. Chiorazzi, and P. K. A. Mongini (2012)
J. Immunol. 188, 6093-6108
   Abstract »    Full Text »    PDF »
Ataxia-Telangiectasia, Mutated (ATM)/Nuclear Factor {kappa} Light Chain Enhancer of Activated B Cells (NF{kappa}B) Signaling Controls Basal and DNA Damage-induced Transglutaminase 2 Expression.
L. Ai, R. R. Skehan, J. Saydi, T. Lin, and K. D. Brown (2012)
J. Biol. Chem. 287, 18330-18341
   Abstract »    Full Text »    PDF »
Regulation of intracellular signalling through cysteine oxidation by reactive oxygen species.
H. Miki and Y. Funato (2012)
J. Biochem. 151, 255-261
   Abstract »    Full Text »    PDF »
Regulation by S-Nitrosylation of Protein Post-translational Modification.
D. T. Hess and J. S. Stamler (2012)
J. Biol. Chem. 287, 4411-4418
   Abstract »    Full Text »    PDF »
Mitochondrial dysfunction in ataxia-telangiectasia.
Y. A. Valentin-Vega, K. H. MacLean, J. Tait-Mulder, S. Milasta, M. Steeves, F. C. Dorsey, J. L. Cleveland, D. R. Green, and M. B. Kastan (2012)
Blood 119, 1490-1500
   Abstract »    Full Text »    PDF »
High Throughput Short Interfering RNA (siRNA) Screening of the Human Kinome Identifies Novel Kinases Controlling the Canonical Nuclear Factor-{kappa}B (NF-{kappa}B) Activation Pathway.
S. Choudhary, K. P. Rosenblatt, L. Fang, B. Tian, Z.-H. Wu, and A. R. Brasier (2011)
J. Biol. Chem. 286, 37187-37195
   Abstract »    Full Text »    PDF »
Regulator of G Protein Signaling 6 Mediates Doxorubicin-Induced ATM and p53 Activation by a Reactive Oxygen Species-Dependent Mechanism.
J. Huang, J. Yang, B. Maity, D. Mayuzumi, and R. A. Fisher (2011)
Cancer Res. 71, 6310-6319
   Abstract »    Full Text »    PDF »
ATM Protein-dependent Phosphorylation of Rad50 Protein Regulates DNA Repair and Cell Cycle Control.
M. Gatei, B. Jakob, P. Chen, A. W. Kijas, O. J. Becherel, N. Gueven, G. Birrell, J.-H. Lee, T. T. Paull, Y. Lerenthal, et al. (2011)
J. Biol. Chem. 286, 31542-31556
   Abstract »    Full Text »    PDF »
Signal transduction by reactive oxygen species.
T. Finkel (2011)
J. Cell Biol. 194, 7-15
   Abstract »    Full Text »    PDF »
Isoform-specific regulation of Akt by PDGF-induced reactive oxygen species.
R. Wani, J. Qian, L. Yin, E. Bechtold, S. B. King, L. B. Poole, E. Paek, A. W. Tsang, and C. M. Furdui (2011)
PNAS 108, 10550-10555
   Abstract »    Full Text »    PDF »
Functional relevance of the histone {gamma}H2Ax in the response to DNA damaging agents.
I. Revet, L. Feeney, S. Bruguera, W. Wilson, T. K. Dong, D. H. Oh, D. Dankort, and J. E. Cleaver (2011)
PNAS 108, 8663-8667
   Abstract »    Full Text »    PDF »
DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction.
M. Ardolino, A. Zingoni, C. Cerboni, F. Cecere, A. Soriani, M. L. Iannitto, and A. Santoni (2011)
Blood 117, 4778-4786
   Abstract »    Full Text »    PDF »
Aprataxin localizes to mitochondria and preserves mitochondrial function.
P. Sykora, D. L. Croteau, V. A. Bohr, and D. M. Wilson III (2011)
PNAS 108, 7437-7442
   Abstract »    Full Text »    PDF »
Investigation of the Functional Link between ATM and NBS1 in the DNA Damage Response in the Mouse Cerebellum.
I. Dar, G. Yosha, R. Elfassy, R. Galron, Z.-Q. Wang, Y. Shiloh, and A. Barzilai (2011)
J. Biol. Chem. 286, 15361-15376
   Abstract »    Full Text »    PDF »
Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere-independent mechanism.
E. Nitta, M. Yamashita, K. Hosokawa, M. Xian, K. Takubo, F. Arai, S. Nakada, and T. Suda (2011)
Blood 117, 4169-4180
   Abstract »    Full Text »    PDF »
ATM Is a Redox Sensor Linking Genome Stability and Carbon Metabolism.
A. Kruger and M. Ralser (2011)
Science Signaling 4, pe17
   Abstract »    Full Text »    PDF »
All Stressed Out Without ATM Kinase.
J. J. P. Perry and J. A. Tainer (2011)
Science Signaling 4, pe18
   Abstract »    Full Text »    PDF »
Autophosphorylation and ATM Activation: ADDITIONAL SITES ADD TO THE COMPLEXITY.
S. V. Kozlov, M. E. Graham, B. Jakob, F. Tobias, A. W. Kijas, M. Tanuji, P. Chen, P. J. Robinson, G. Taucher-Scholz, K. Suzuki, et al. (2011)
J. Biol. Chem. 286, 9107-9119
   Abstract »    Full Text »    PDF »
Signals from the Nucleus: Activation of NF-{kappa}B by Cytosolic ATM in the DNA Damage Response.
K. Hadian and D. Krappmann (2011)
Science Signaling 4, pe2
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882