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A more recent version of this article appeared on September 19, 2003
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Papers In Press, published online ahead of print July 3, 2003
J. Biol. Chem, 10.1074/jbc.M306500200
Submitted on June 19, 2003
Revised on July 3, 2003
Accepted on July 3, 2003

Hypersensitivity of NHEJ mutants to VP-16 and ICRF-193: Implications for the repair of topoisomerase II-mediated DNA damage

Noritaka Adachi, Hiromi Suzuki, Susumu Iiizumi, and Hideki Koyama

Kihara Institute Biology Research, Yokohama City University, Yokohama 244-0813

Corresponding Author: nadachi{at}yokohama-cu.ac.jp

A number of clinically useful anticancer drugs, including etoposide (VP-16), target DNA topoisomerase (topo) II. These drugs, referred to as topo II poisons, stabilize cleavable (or cleavage) complexes, thereby generating DNA double-strand breaks (DSBs). Bis(2,6-dioxopiperazine)s such as ICRF-193 also inhibit topo II, by inducing a distinct type of DNA damage, termed topo II clamps, which has been believed to be devoid of DSBs. Despite the biological and clinical importance, the molecular mechanisms for the repair of topo II-mediated DNA damage remain largely unknown. Here, we perform genetic analyses using the chicken DT40 cell line to investigate how DNA lesions caused by topo II inhibitors are repaired. Notably, we show that LIG4/ and KU70/ cells, which are defective in nonhomologous DNA end-joining (NHEJ), are extremely sensitive to both VP-16 and ICRF-193. In contrast, RAD54/ cells (defective in homologous recombination) are much less hypersensitive to VP-16 than the NHEJ mutants and, more importantly, are not hypersensitive to ICRF-193. Our results provide the first evidence that NHEJ is the predominant pathway for the repair of topo II-mediated DNA damagecleavable complexes and topo II clamps. The outstandingly increased cytotoxicity of topo II inhibitors in the absence of NHEJ suggests that simultaneous inhibition of topo II and NHEJ would provide a powerful protocol in cancer chemotherapy involving topo II inhibitors.


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