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Published online 17 April 2006. doi:10.1083/jcb.200510130
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 2, 195-206
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Article

 Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks

Simon Bekker-Jensen1, Claudia Lukas1, Risa Kitagawa2,3, Fredrik Melander1, Michael B. Kastan2, Jiri Bartek1, and Jiri Lukas1

1 Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
2 Department of Hematology-Oncology and 3 Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38105

Correspondence to Jiri Lukas: jil{at}cancer.dk; or Claudia Lukas: clukas{at}cancer.dk

We show that DNA double-strand breaks (DSBs) induce complex subcompartmentalization of genome surveillance regulators. Chromatin marked by {gamma}-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.

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.


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