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First published online November 19, 2008
doi: 10.1242/10.1242/jcs.033688

Journal of Cell Science 121, 3933-3940 (2008)
Published by The Company of Biologists 2008
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Research Article

ATR and Rad17 collaborate in modulating Rad9 localisation at sites of DNA damage

Annette L. Medhurst1,*, Daniël O. Warmerdam2,*, Ildem Akerman1, Edward H. Verwayen2, Roland Kanaar2,3, Veronique A. J. Smits2,{ddagger},§ and Nicholas D. Lakin1,§

1 Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QD, UK
2 Department of Cell Biology and Genetics, Cancer Genome Center, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands
3 Department of Radiation Oncology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands

§ Author for correspondence (e-mail: vsmits{at}ull.es)

§ Author for correspondence (e-mail: nicholas.lakin{at}bioch.ox.ac.uk)

Accepted 2 September 2008

The cell cycle checkpoint kinase Chk1 is phosphorylated and activated by ATR in response to DNA damage and is crucial for initiating the DNA damage response. A number of factors act in concert with ATR to facilitate Chk1 phosphorylation, including Rad17-RFC, the Rad9-Rad1-Hus1 complex, TopBP1 and Claspin. Rad17 is required for loading of Rad9-Rad1-Hus1 (9-1-1) onto sites of DNA damage. Although phosphorylation of Rad17 by ATR is required for checkpoint function, how this affects 9-1-1 regulation remains unclear. We report that exposure of cells to DNA damage or replication stress results in Rad17-dependent immobilisation of Rad9 into nuclear foci. Furthermore, expression of mutant Rad17 that cannot be phosphorylated by ATR (Rad17AA), or downregulation of ATR, results in a decreased number of cells that display Rad9 foci. Photobleaching experiments reveal an increase in the dynamic behaviour of Rad9 within remaining foci in the absence of ATR or following expression of Rad17AA. Together, these data suggest a model in which Rad17 and ATR collaborate in regulating Rad9 localisation and association at sites of DNA damage.

Key words: ATR, DNA-damage signalling, Cell cycle checkpoints, Genome stability, Rad9


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JCS 2008 121: 2304. [Full Text]  





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