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Vol. 19, Issue 9, 3923-3933, September 2008

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WRN Is Required for ATM Activation and the S-Phase Checkpoint in Response to Interstrand Cross-Link–Induced DNA Double-Strand Breaks

Wen-Hsing Cheng^*,, Diana Muftic^*,, Meltem Muftuoglu^*, Lale Dawut^*, Christa Morris, Thomas Helleday, Yosef Shiloh^||, and Vilhelm A. Bohr^*

*Laboratory of Molecular Gerontology and Flow Cytometry Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742; Department of Genetics, Microbiology, and Toxicology, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden; and ^||David and Inez Myers Laboratory for Genetic Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Submitted July 25, 2007; Revised April 25, 2008; Accepted June 20, 2008
Monitoring Editor: Yixian Zheng

Werner syndrome (WS) is a human genetic disorder characterized by extensive clinical features of premature aging. Ataxia-telengiectasia (A-T) is a multisystem human genomic instability syndrome that includes premature aging in some of the patients. WRN and ATM, the proteins defective in WS and A-T, respectively, play significant roles in the maintenance of genomic stability and are involved in several DNA metabolic pathways. A role for WRN in DNA repair has been proposed; however, this study provides evidence that WRN is also involved in ATM pathway activation and in a S-phase checkpoint in cells exposed to DNA interstrand cross-link–induced double-strand breaks. Depletion of WRN in such cells by RNA interference results in an intra-S checkpoint defect, and interferes with activation of ATM as well as downstream phosphorylation of ATM target proteins. Treatment of cells under replication stress with the ATM kinase inhibitor KU 55933 results in a S-phase checkpoint defect similar to that observed in WRN shRNA cells. Moreover, H2AX levels are higher in WRN shRNA cells than in control cells 6 and 16 h after exposure to psoralen DNA cross-links. These results suggest that WRN and ATM participate in a replication checkpoint response, in which WRN facilitates ATM activation in cells with psoralen DNA cross-link–induced collapsed replication forks.

Address correspondence to: Vilhelm A. Bohr (vbohr{at}nih.gov)

Abbreviations used: A-T, ataxia-telengiectasia A-T; CPT, camptothecin; DSBs, double-strand breaks; HU, hydroxyurea; ICLs, interstrand cross-links; MRN, Mre11-Rad50-Nbs1; PUVA, psoralen plus UVA; PFGE, pulse-field gel electrophoresis; WS, Werner syndrome; WRN, Werner protein.

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