西亞試劑：Rapid activation of ATM on DNA flanking double-strand break

Rapid activation of ATM on DNA flanking double-strand breaks

Zhongsheng You1, Julie M. Bailis1, Sam A. Johnson1, Stephen M. Dilworth2 & Tony Hunter1

1  Molecular and Cell Biology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

2  Department of Metabolic Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.

Correspondence should be addressed to Tony Hunter hunter@salk.edu

The tumour-suppressor gene ATM, mutations in which cause the human genetic disease ataxia telangiectasia (A-T), encodes a key protein kinase that controls the cellular response to DNA double-strand breaks (DSBs)1, 2. DNA DSBs caused by ionizing radiation or chemicals result in rapid ATM autophosphorylation, leading to checkpoint activation and phosphorylation of substrates that regulate cell-cycle progression, DNA repair, transcription and cell death3. However, the precise mechanism by which damaged DNA induces ATM and checkpoint activation remains unclear. Here, we demonstrate that linear DNA fragments added to Xenopus egg extracts mimic DSBs in genomic DNA and provide a platform for ATM autophosphorylation and activation. ATM autophosphorylation and phosphorylation of its substrate NBS1 are dependent on DNA fragment length and the concentration of DNA ends. The minimal DNA length required for efficient ATM autophosphorylation is 200 base pairs, with cooperative autophosphorylation induced by DNA fragments of at least 400 base pairs. Importantly, full ATM activation requires it to bind to DNA regions flanking DSB ends. These findings reveal a direct role for DNA flanking DSB ends in ATM activation.

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