Rapid activation of ATM on DNA flanking double-strand breaks

Article


You, Z., Bailis, J., Johnson, S., Dilworth, S. and Hunter, T. 2007. Rapid activation of ATM on DNA flanking double-strand breaks. Nature Cell Biology. 9 (11), pp. 1311-1318. https://doi.org/10.1038/ncb1651
TypeArticle
TitleRapid activation of ATM on DNA flanking double-strand breaks
AuthorsYou, Z., Bailis, J., Johnson, S., Dilworth, S. and Hunter, T.
Abstract

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). 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 death. 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 approximately 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.

Research GroupMolecular Biology group
PublisherNature Publishing Group
JournalNature Cell Biology
ISSN1465-7392
Publication dates
PrintNov 2007
Publication process dates
Deposited19 Feb 2013
Output statusPublished
Digital Object Identifier (DOI)https://doi.org/10.1038/ncb1651
LanguageEnglish
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