Letter abstract
Nature Cell Biology 5, 255 - 260 (2003)
Published online: 24 February 2003 | doi:10.1038/ncb945
Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage
Claudia Lukas1,2, Jacob Falck1,2, Jirina Bartkova1, Jiri Bartek1 & Jiri Lukas1
Cell cycle checkpoints are signal transduction pathways activated after DNA damage to protect genomic integrity1. Dynamic spatiotemporal coordination is a vital, but poorly understood aspect, of these checkpoints. Here, we provide evidence for a strikingly different behaviour of Chk2 versus Nbs1, key mediators of the ataxia-telangiecatesia-mutated (ATM)-controlled checkpoint pathways induced by DNA double-strand breaks (DSBs)1, 2. In live human cells with DSBs restricted to small sub-nuclear areas, Nbs1 was rapidly recruited to the damaged regions and underwent a dynamic exchange in the close vicinity of the DSB sites. In contrast, Chk2 continued to rapidly move throughout the entire nucleus, irrespective of DNA damage and including the DSB-free areas. Although phosphorylation of Chk2 by ATM occurred exclusively at the DSB sites, forced immobilization of Chk2 to spatially restricted, DSB-containing nuclear areas impaired its stimulating effect on p53-dependent transcription. These results unravel a dynamic nature of Nbs1 interaction with DSB lesions and identify Chk2 as a candidate transmitter of the checkpoint signal, allowing for a coordinated pan-nuclear response to focal DNA damage.
- Danish Cancer Society, Institute of Cancer Biology, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
- These authors contributed equally to this work.
Correspondence to: Jiri Lukas1 e-mail: lukas@biobase.dk
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