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Werner Protein Protects Nonproliferating Cells from Oxidative DNA Damage

Anna M. Szekely,^1,2 Franziska Bleichert,¹ Astrid Nümann,^1, Stephen Van Komen,¹ Elisabeth Manasanch,^1,¶ Abdelhakim Ben Nasr,^1, Allon Canaan,¹ and Sherman M. Weissman^1*

Department of Genetics,¹ Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510²

Received 1 December 2004/ Returned for modification 10 January 2005/ Accepted 31 August 2005

Werner syndrome, caused by mutations of the WRN gene, mimics many changes of normal aging. Although roles for WRN protein in DNA replication, recombination, and telomere maintenance have been suggested, the pathology of rapidly dividing cells is not a feature of Werner syndrome. To identify cellular events that are specifically vulnerable to WRN deficiency, we used RNA interference (RNAi) to knockdown WRN or BLM (the RecQ helicase mutated in Bloom syndrome) expression in primary human fibroblasts. Withdrawal of WRN or BLM produced accelerated cellular senescence phenotype and DNA damage response in normal fibroblasts, as evidenced by induction of H2AX and 53BP1 nuclear foci. After WRN depletion, the induction of these foci was seen most prominently in nondividing cells. Growth in physiological (3%) oxygen or in the presence of an antioxidant prevented the development of the DNA damage foci in WRN-depleted cells, whereas acute oxidative stress led to inefficient repair of the lesions. Furthermore, WRN RNAi-induced DNA damage was suppressed by overexpression of the telomere-binding protein TRF2. These conditions, however, did not prevent the DNA damage response in BLM-ablated cells, suggesting a distinct role for WRN in DNA homeostasis in vivo. Thus, manifestations of Werner syndrome may reflect an impaired ability of slowly dividing cells to limit oxidative DNA damage.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Institut für Neuropathologie, Charité-Humboldt Universität, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany.

^¶ Present address: University of Barcelona, Tapineria 10, 2, 08002 Barcelona, Spain.

Present address: Department of Immunology and Microbiology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555.

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