Identification of the interferon-inducible double-stranded RNA-dependent protein kinase as a regulator of cellular response to bulky adducts

The double-stranded RNA-dependent protein kinase PKR plays a central role i n IFN-mediated antiviral response. The ability of PKR mutants to transform rodent fibroblasts led to the hypothesis that PKR acts as a tumor suppresso r. Recent studies have identified an expanding network of PKR signaling par tners, including signal transducers and activators of transcription 1 (STAT 1), p53, and I kappaB-kinase, Here we demonstrate that PKR is involved in t he cellular response to genotoxic stress. PKR-deficient mouse-embryonic fib roblasts (PKR-/-) are hypersensitive to bulky adduct DNA damage caused by c isplatin, 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 kine tics. Most strikingly, PKR localizes to the nucleus rapidly upon cisplatin treatment. Restoration of PKR in PKR-/- cells results in resistance to cisp latin and enhanced cell capacity to remove cisplatin DNA adducts, We conclu de that PKR has a function in the regulation of cellular response to bulky adduct-inducing agents, possibly by modulating DNA repair mechanisms.