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Interplay between ATM and ATR in the regulation of common fragile site stability

Abstract

Common fragile sites are specific genomic loci that form constrictions and gaps on metaphase chromosomes under conditions that slow, but do not arrest, DNA replication. These sites have been shown to have a role in various chromosomal rearrangements in tumors. Different DNA damage response proteins were shown to regulate fragile site stability, including ataxia-telangiectasia and Rad3-related (ATR) and its effector Chk1. Here, we investigated the role of ataxia-telangiectasia mutated (ATM), the main transducer of DNA double-strand break (DSB) signal, in this regulation. We demonstrate that replication stress conditions, which induce fragile site expression, lead to DNA fragmentation and recruitment of phosphorylated ATM to nuclear foci at DSBs. We further show that ATM plays a role in maintaining fragile site stability, which is revealed only in the absence of ATR. However, the activation of ATM under these replication stress conditions is ATR independent. Following conditions that induce fragile site expression both ATR and ATM phosphorylate Chk1, suggesting that both proteins regulate fragile site expression probably via their effect on Chk1 activation. Our findings provide new insights into the interplay between ATR and ATM pathways in response to partial replication inhibition and in the regulation of fragile site stability.

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Acknowledgements

We thank Naomi Melamed-Book for assistance in confocal analyses, Yifat Eliezer for assistance in western blot analyses, Y Shiloh and Y Ziv for comments on the manuscript, the AT fibroblast cell line (AT22IJE-T) and ATM complemented cells and for the ATM antibody.

This research was partially supported by grants from the Ministry of Science and Technology Israel, the Deutsches Krebsforschungszetrum (DKFZ) and the Israel Cancer Association through the donation from Linda R Kaminow in honor of Ed Fox to BK

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Correspondence to B Kerem.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Ozeri-Galai, E., Schwartz, M., Rahat, A. et al. Interplay between ATM and ATR in the regulation of common fragile site stability. Oncogene 27, 2109–2117 (2008). https://doi.org/10.1038/sj.onc.1210849

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