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Identification of the Interferon-inducible Double-Stranded RNA-dependent Protein Kinase as a Regulator of Cellular Response to Bulky Adducts¹

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Departments of Medicine and Oncology [J. B., N. B., A. E. K., M. A. A-J.], Pharmacology and Therapeutics [M. A. A-J.], Division of Experimental Medicine [P. J. S., A. E. K., M. A. A-J.], and McGill Centre for Translational Research in Cancer [M. A. A-J.], McGill University, Montreal, Quebec, H3T 1E2 Canada

The double-stranded RNA-dependent protein kinase PKR plays a central role in IFN-mediated antiviral response. The ability of PKR mutants to transform rodent fibroblasts led to the hypothesis that PKR acts as a tumor suppressor. Recent studies have identified an expanding network of PKR signaling partners, including signal transducers and activators of transcription 1 (STAT1), p53, and IB-kinase. Here we demonstrate that PKR is involved in the cellular response to genotoxic stress. PKR-deficient mouse-embryonic fibroblasts (PKR^-/-) are hypersensitive to bulky adduct DNA damage caused by cisplatin, melphalan, and UV radiation but not to other DNA-damaging agents such as Adriamycin. PKR-deficient cells are highly susceptible to cisplatin-induced apoptosis. They demonstrate retarded cisplatin adduct removal kinetics. Most strikingly, PKR localizes to the nucleus rapidly upon cisplatin treatment. Restoration of PKR in PKR^-/- cells results in resistance to cisplatin and enhanced cell capacity to remove cisplatin DNA adducts. We conclude that PKR has a function in the regulation of cellular response to bulky adduct-inducing agents, possibly by modulating DNA repair mechanisms.

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