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Nucleic Acids Research Advance Access first published online on November 29, 2007
This version published online on December 20, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm1052
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

ATR-dependent pathways control hEXO1 stability in response to stalled forks

Mahmoud El-Shemerly1, Daniel Hess2, Aswin K. Pyakurel1, Said Moselhy1 and Stefano Ferrari1,*

1Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich and 2Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland

*To whom correspondence should be addressed. Tel: +41 44 635 3471; Fax: +41 44 635 3484; Email: sferrari{at}imcr.uzh.ch

Received October 18, 2007. Accepted November 5, 2007.

Nucleases play important roles in DNA synthesis, recombination and repair. We have previously shown that human exonuclease 1 (hEXO1) is phosphorylated in response to agents stalling DNA replication and that hEXO1 consequently undergoes ubiquitination and degradation in a proteasome-dependent manner. In the present study, we have addressed the identity of the pathway transducing stalled-replication signals to hEXO1. Using chemical inhibitors, RNA interference, ATM- and ATR-deficient cell lines we have concluded that hEXO1 phosphorylation is ATR-dependent. By means of mass spectrometry, we have identified the sites of phosphorylation in hEXO1 in undamaged cells and in cells treated with hydroxyurea (HU). hEXO1 is phosphorylated at nine basal sites and three additional sites are induced by HU treatment. Analysis of single- and multiple-point mutants revealed that mutation to Ala of the three HU-induced sites of phosphorylation partially rescued HU-dependent degradation of hEXO1 and additionally stabilized the protein in non-treated cells. We have raised an antibody to pS714, an HU-induced site of the S/T-Q type, and we provide evidence that S714 is phosphorylated upon HU but not IR treatment. The antibody may be a useful tool to monitor signal transduction events triggered by stalled DNA replication.

Present address: Said Moselhy, Department of Biochemistry, Faculty of Science, Aim-Shams University, Abbassia, Cairo, Egypt.


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