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 320 (5882): 1507-1510

Copyright © 2008 by the American Association for the Advancement of Science

Activation of the Cellular DNA Damage Response in the Absence of DNA Lesions

Evi Soutoglou, and Tom Misteli

Abstract: The cellular DNA damage response (DDR) is initiated by the rapid recruitment of repair factors to the site of DNA damage to form a multiprotein repair complex. How the repair complex senses damaged DNA and then activates the DDR is not well understood. We show that prolonged binding of DNA repair factors to chromatin can elicit the DDR in an ATM (ataxia telangiectasia mutated)– and DNAPK (DNA-dependent protein kinase)–dependent manner in the absence of DNA damage. Targeting of single repair factors to chromatin revealed a hierarchy of protein interactions within the repair complex and suggests amplification of the damage signal. We conclude that activation of the DDR does not require DNA damage and stable association of repair factors with chromatin is likely a critical step in triggering, amplifying, and maintaining the DDR signal.

National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. E-mail: mistelit{at}mail.nih.gov (T.M.); soutogle{at}mail.nih.gov (E.S.)

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition.
D. S. Kirkpatrick, D. J. Bustos, T. Dogan, J. Chan, L. Phu, A. Young, L. S. Friedman, M. Belvin, Q. Song, C. E. Bakalarski, et al. (2013)
PNAS 110, 19426-19431
   Abstract »    Full Text »    PDF »
DNA double-strand-break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice.
A. Schipler and G. Iliakis (2013)
Nucleic Acids Res. 41, 7589-7605
   Abstract »    Full Text »    PDF »
Lysosome-mediated processing of chromatin in senescence.
A. Ivanov, J. Pawlikowski, I. Manoharan, J. van Tuyn, D. M. Nelson, T. S. Rai, P. P. Shah, G. Hewitt, V. I. Korolchuk, J. F. Passos, et al. (2013)
J. Cell Biol. 202, 129-143
   Abstract »    Full Text »    PDF »
An autonomous chromatin/DNA-PK mechanism for localized DNA damage signaling in mammalian cells.
D. P. Munoz, M. Kawahara, and S. M. Yannone (2013)
Nucleic Acids Res. 41, 2894-2906
   Abstract »    Full Text »    PDF »
Engagement of the ATR-Dependent DNA Damage Response at the Human Papillomavirus 18 Replication Centers during the Initial Amplification.
T. Reinson, M. Toots, M. Kadaja, R. Pipitch, M. Allik, E. Ustav, and M. Ustav (2013)
J. Virol. 87, 951-964
   Abstract »    Full Text »    PDF »
Charting the Landscape of Tandem BRCT Domain-Mediated Protein Interactions.
N. T. Woods, R. D. Mesquita, M. Sweet, M. A. Carvalho, X. Li, Y. Liu, H. Nguyen, C. E. Thomas, E. S. Iversen Jr., S. Marsillac, et al. (2012)
Science Signaling 5, rs6
   Abstract »    Full Text »    PDF »
Human Papillomaviruses Recruit Cellular DNA Repair and Homologous Recombination Factors to Viral Replication Centers.
K. A. Gillespie, K. P. Mehta, L. A. Laimins, and C. A. Moody (2012)
J. Virol. 86, 9520-9526
   Abstract »    Full Text »    PDF »
A new non-catalytic role for ubiquitin ligase RNF8 in unfolding higher-order chromatin structure.
M. S. Luijsterburg, K. Acs, L. Ackermann, W. W. Wiegant, S. Bekker-Jensen, D. H. Larsen, K. K. Khanna, H. van Attikum, N. Mailand, and N. P. Dantuma (2012)
EMBO J. 31, 2511-2527
   Abstract »    Full Text »    PDF »
DDB2 promotes chromatin decondensation at UV-induced DNA damage.
M. S. Luijsterburg, M. Lindh, K. Acs, M. G. Vrouwe, A. Pines, H. van Attikum, L. H. Mullenders, and N. P. Dantuma (2012)
J. Cell Biol. 197, 267-281
   Abstract »    Full Text »    PDF »
Recognition of DNA damage by XPC coincides with disruption of the XPC-RAD23 complex.
S. Bergink, W. Toussaint, M. S. Luijsterburg, C. Dinant, S. Alekseev, J. H. J. Hoeijmakers, N. P. Dantuma, A. B. Houtsmuller, and W. Vermeulen (2012)
J. Cell Biol. 196, 681-688
   Abstract »    Full Text »    PDF »
The NF90/NF45 Complex Participates in DNA Break Repair via Nonhomologous End Joining.
R. A. Shamanna, M. Hoque, A. Lewis-Antes, E. I. Azzam, D. Lagunoff, T. Pe'ery, and M. B. Mathews (2011)
Mol. Cell. Biol. 31, 4832-4843
   Abstract »    Full Text »    PDF »
De novo assembly of a PML nuclear subcompartment occurs through multiple pathways and induces telomere elongation.
I. Chung, H. Leonhardt, and K. Rippe (2011)
J. Cell Sci. 124, 3603-3618
   Abstract »    Full Text »    PDF »
Lac operator repeats generate a traceable fragile site in mammalian cells.
A. Jacome and O. Fernandez-Capetillo (2011)
EMBO Rep. 12, 1032-1038
   Abstract »    Full Text »    PDF »
Nuclear Accumulation of the Papillomavirus E1 Helicase Blocks S-Phase Progression and Triggers an ATM-Dependent DNA Damage Response.
A. Fradet-Turcotte, F. Bergeron-Labrecque, C. A. Moody, M. Lehoux, L. A. Laimins, and J. Archambault (2011)
J. Virol. 85, 8996-9012
   Abstract »    Full Text »    PDF »
Distinct Properties of Human HMGN5 Reveal a Rapidly Evolving but Functionally Conserved Nucleosome Binding Protein.
C. Malicet, M. Rochman, Y. Postnikov, and M. Bustin (2011)
Mol. Cell. Biol. 31, 2742-2755
   Abstract »    Full Text »    PDF »
Kinetics of {gamma}-H2AX induction and removal in bone marrow and testicular cells of mice after X-ray irradiation.
L. Paris, E. Cordelli, P. Eleuteri, M. G. Grollino, E. Pasquali, R. Ranaldi, R. Meschini, and F. Pacchierotti (2011)
Mutagenesis 26, 563-572
   Abstract »    Full Text »    PDF »
Tethering DNA Damage Checkpoint Mediator Proteins Topoisomerase II{beta}-binding Protein 1 (TopBP1) and Claspin to DNA Activates Ataxia-Telangiectasia Mutated and RAD3-related (ATR) Phosphorylation of Checkpoint Kinase 1 (Chk1).
L. A. Lindsey-Boltz and A. Sancar (2011)
J. Biol. Chem. 286, 19229-19236
   Abstract »    Full Text »    PDF »
A DNA-dependent stress response involving DNA-PK occurs in hypoxic cells and contributes to cellular adaptation to hypoxia.
F. Bouquet, M. Ousset, D. Biard, F. Fallone, S. Dauvillier, P. Frit, B. Salles, and C. Muller (2011)
J. Cell Sci. 124, 1943-1951
   Abstract »    Full Text »    PDF »
The DNA Damage Response Signaling Cascade Regulates Proliferation of the Phytopathogenic Fungus Ustilago maydis in Planta.
C. de Sena-Tomas, A. Fernandez-Alvarez, W. K. Holloman, and J. Perez-Martin (2011)
PLANT CELL 23, 1654-1665
   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 »
On emerging nuclear order.
I. Rajapakse and M. Groudine (2011)
J. Cell Biol. 192, 711-721
   Abstract »    Full Text »    PDF »
Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications.
S. E. Polo and S. P. Jackson (2011)
Genes & Dev. 25, 409-433
   Abstract »    Full Text »    PDF »
Extranuclear protection of chromosomal DNA from oxidative stress.
S. Vanderauwera, N. Suzuki, G. Miller, B. van de Cotte, S. Morsa, J.-L. Ravanat, A. Hegie, C. Triantaphylides, V. Shulaev, M. C. E. Van Montagu, et al. (2011)
PNAS 108, 1711-1716
   Abstract »    Full Text »    PDF »
DNA Damage Response.
G. Giglia-Mari, A. Zotter, and W. Vermeulen (2011)
Cold Spring Harb Perspect Biol 3, a000745
   Abstract »    Full Text »    PDF »
Phosphorylation of p50 NF-{kappa}B at a Single Serine Residue by DNA-dependent Protein Kinase Is Critical for VCAM-1 Expression upon TNF Treatment.
J. Ju, A. S. Naura, Y. Errami, M. Zerfaoui, H. Kim, J. G. Kim, Z. Y. Abd Elmageed, A. B. Abdel-Mageed, C. Giardina, A. A. Beg, et al. (2010)
J. Biol. Chem. 285, 41152-41160
   Abstract »    Full Text »    PDF »
Rsf-1, a Chromatin Remodeling Protein, Induces DNA Damage and Promotes Genomic Instability.
J. J.-C. Sheu, B. Guan, J.-H. Choi, A. Lin, C.-H. Lee, Y.-T. Hsiao, T.-L. Wang, F.-J. Tsai, and I.-M. Shih (2010)
J. Biol. Chem. 285, 38260-38269
   Abstract »    Full Text »    PDF »
Alternative Cyclin D1 Splice Forms Differentially Regulate the DNA Damage Response.
Z. Li, X. Jiao, C. Wang, L. A. Shirley, H. Elsaleh, O. Dahl, M. Wang, E. Soutoglou, E. S. Knudsen, and R. G. Pestell (2010)
Cancer Res. 70, 8802-8811
   Abstract »    Full Text »    PDF »
The Viral Oncoprotein Tax Sequesters DNA Damage Response Factors by Tethering MDC1 to Chromatin.
S. M. Belgnaoui, K. A. Fryrear, J. O. Nyalwidhe, X. Guo, and O. J. Semmes (2010)
J. Biol. Chem. 285, 32897-32905
   Abstract »    Full Text »    PDF »
Tumors induce complex DNA damage in distant proliferative tissues in vivo.
C. E. Redon, J. S. Dickey, A. J. Nakamura, I. G. Kareva, D. Naf, S. Nowsheen, T. B. Kryston, W. M. Bonner, A. G. Georgakilas, and O. A. Sedelnikova (2010)
PNAS 107, 17992-17997
   Abstract »    Full Text »    PDF »
Multiple DNA Damage Signaling and Repair Pathways Deregulated by Simian Virus 40 Large T Antigen.
S. Boichuk, L. Hu, J. Hein, and O. V. Gjoerup (2010)
J. Virol. 84, 8007-8020
   Abstract »    Full Text »    PDF »
Reconstitution of RPA-covered single-stranded DNA-activated ATR-Chk1 signaling.
J.-H. Choi, L. A. Lindsey-Boltz, M. Kemp, A. C. Mason, M. S. Wold, and A. Sancar (2010)
PNAS 107, 13660-13665
   Abstract »    Full Text »    PDF »
HIV-1 Vpr Induces the K48-Linked Polyubiquitination and Proteasomal Degradation of Target Cellular Proteins To Activate ATR and Promote G2 Arrest.
J.-P. Belzile, J. Richard, N. Rougeau, Y. Xiao, and E. A. Cohen (2010)
J. Virol. 84, 3320-3330
   Abstract »    Full Text »    PDF »
Involvement of p29 in DNA damage responses and Fanconi anemia pathway.
P.-C. Chu, T.-Y. Wang, Y.-T. Lu, C.-K. Chou, Y.-C. Yang, and M.-S. Chang (2009)
Carcinogenesis 30, 1710-1716
   Abstract »    Full Text »    PDF »
Radiation-induced mitotic catastrophe in PARG-deficient cells.
J.-C. Ame, E. Fouquerel, L. R. Gauthier, D. Biard, F. D. Boussin, F. Dantzer, G. de Murcia, and V. Schreiber (2009)
J. Cell Sci. 122, 1990-2002
   Abstract »    Full Text »    PDF »
H2AX Is Required for Cell Cycle Arrest via the p53/p21 Pathway.
M. Fragkos, J. Jurvansuu, and P. Beard (2009)
Mol. Cell. Biol. 29, 2828-2840
   Abstract »    Full Text »    PDF »
The emergence of lineage-specific chromosomal topologies from coordinate gene regulation.
I. Rajapakse, M. D. Perlman, D. Scalzo, C. Kooperberg, M. Groudine, and S. T. Kosak (2009)
PNAS 106, 6679-6684
   Abstract »    Full Text »    PDF »
DNA Ligase I Deficiency Leads to Replication-Dependent DNA Damage and Impacts Cell Morphology without Blocking Cell Cycle Progression.
S. Soza, V. Leva, R. Vago, G. Ferrari, G. Mazzini, G. Biamonti, and A. Montecucco (2009)
Mol. Cell. Biol. 29, 2032-2041
   Abstract »    Full Text »    PDF »
Assembly of multiprotein complexes that control genome function.
C. Dinant, M. S. Luijsterburg, T. Hofer, G. von Bornstaedt, W. Vermeulen, A. B. Houtsmuller, and R. van Driel (2009)
J. Cell Biol. 185, 21-26
   Abstract »    Full Text »    PDF »
Chromatin-associated proteins HMGB1/2 and PDIA3 trigger cellular response to chemotherapy-induced DNA damage.
N. F. Krynetskaia, M. S. Phadke, S. H. Jadhav, and E. Y. Krynetskiy (2009)
Mol. Cancer Ther. 8, 864-872
   Abstract »    Full Text »    PDF »
Tdp1 protects against oxidative DNA damage in non-dividing fission yeast.
S. Ben Hassine and B. Arcangioli (2009)
EMBO J. 28, 632-640
   Abstract »    Full Text »    PDF »
{gamma}-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin.
A. Kinner, W. Wu, C. Staudt, and G. Iliakis (2008)
Nucleic Acids Res. 36, 5678-5694
   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