We show that DNA double-strand breaks (DSBs) induce complex subcompartmentalization of genome surveillance regulators. Chromatin marked by γ-H2AX is occupied by ataxia telangiectasia–mutated (ATM) kinase, Mdc1, and 53BP1. In contrast, repair factors (Rad51, Rad52, BRCA2, and FANCD2), ATM and Rad-3–related (ATR) cascade (ATR, ATR interacting protein, and replication protein A), and the DNA clamp (Rad17 and -9) accumulate in subchromatin microcompartments delineated by single-stranded DNA (ssDNA). BRCA1 and the Mre11–Rad50–Nbs1 complex interact with both of these compartments. Importantly, some core DSB regulators do not form cytologically discernible foci. These are further subclassified to proteins that connect DSBs with the rest of the nucleus (Chk1 and -2), that assemble at unprocessed DSBs (DNA-PK/Ku70), and that exist on chromatin as preassembled complexes but become locally modified after DNA damage (Smc1/Smc3). Finally, checkpoint effectors such as p53 and Cdc25A do not accumulate at DSBs at all. We propose that subclassification of DSB regulators according to their residence sites provides a useful framework for understanding their involvement in diverse processes of genome surveillance.
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24 April 2006
Article|
April 17 2006
Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks
In Special Collection:
JCB65: DNA Replication and Repair
Simon Bekker-Jensen,
Simon Bekker-Jensen
1Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
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Claudia Lukas,
Claudia Lukas
1Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
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Risa Kitagawa,
Risa Kitagawa
2Department of Hematology-Oncology
3Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38105
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Fredrik Melander,
Fredrik Melander
1Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
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Michael B. Kastan,
Michael B. Kastan
2Department of Hematology-Oncology
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Jiri Bartek,
Jiri Bartek
1Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
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Jiri Lukas
Jiri Lukas
1Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
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Simon Bekker-Jensen
1Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
Claudia Lukas
1Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
Risa Kitagawa
2Department of Hematology-Oncology
3Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38105
Fredrik Melander
1Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
Michael B. Kastan
2Department of Hematology-Oncology
Jiri Bartek
1Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
Jiri Lukas
1Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
Correspondence to Jiri Lukas: [email protected]; or Claudia Lukas: [email protected]
Abbreviations used in this paper: ATM, ataxia telangiectasia–mutated; ATR, ATM and Rad-3–related; ATRIP, ATR interacting protein; DSB, double-strand break; IR, ionizing radiation; IRIF, IR-induced foci; MRN, Mre11–Rad50–Nbs1 nuclease complex; RPA, replication protein A; ssDNA, single-stranded DNA.
Received:
October 25 2005
Accepted:
March 20 2006
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2006
J Cell Biol (2006) 173 (2): 195–206.
Article history
Received:
October 25 2005
Accepted:
March 20 2006
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Citation
Simon Bekker-Jensen, Claudia Lukas, Risa Kitagawa, Fredrik Melander, Michael B. Kastan, Jiri Bartek, Jiri Lukas; Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks . J Cell Biol 24 April 2006; 173 (2): 195–206. doi: https://doi.org/10.1083/jcb.200510130
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