Werner syndrome cells are sensitive to DNA cross‐linking drugs

Werner Syndrome (WRN) is an autosomal recessive disorder with an elevated risk of cancer resulting from mutations in the WRN DNA helicase/exonuclease gene. Lymphoblastoid cells (LCLs) from WRN patients have previously been shown to have increased toxicity after exposure to 4‐nitroquinoline‐N‐oxide (4NQO) and to camptothecin. Exposure to camptothecin leads to trapping of DNA topoisomerase I molecules onto the DNA, whereas 4NQO may induce diverse forms of chromatin damage. To elucidate the nature of the chromatin lesion(s) to which WRN deficient cells are sensitive, we exposed LCLs to drugs with a spectrum of biochemically defined mechanisms. We found that WRN deficient LCLs show elevated sensitivity to melphalan, chlorambucil, mitomycin C, and cis ‐platinum(II)diammine dichloride, but not to trans ‐platinum(II)diammine dichloride, etoposide, berenil, daunomycin, adriamycin, mitoxantrone, and echinomycin. The drugs to which WRN deficient LCLs are more sensitive all induce apoptosis in S phase and all share the formation of DNA‐interstrand cross‐links as a common biochemical lesion. We hypothesize that cells deficient for WRN function may have a reduced capacity to remove DNA‐interstrand cross‐links, which may lead to apoptosis, increased chromosome aberrations, and cancer in WRN patients.