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J. Biol. Chem., Vol. 279, Issue 36, 37343-37348, September 3, 2004

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Loss of Nonhomologous End Joining Confers Camptothecin Resistance in DT40 Cells

IMPLICATIONS FOR THE REPAIR OF TOPOISOMERASE I-MEDIATED DNA DAMAGE^*

Noritaka Adachi, Sairei So, and Hideki Koyama

From the Kihara Institute for Biological Research, Graduate School of Integrated Science, Yokohama City University, Totsuka-ku, Yokohama 244-0813, Japan

DNA topoisomerase I (Top1) generates transient DNA single-strand breaks via the formation of cleavage complexes in which the enzyme is linked to the 3'-phosphate of the cleavage strand. The anticancer drug camptothecin (CPT) poisons Top1 by trapping cleavage complexes, thereby inducing Top1-linked single-strand breaks. Such DNA lesions are converted into DNA double-strand breaks (DSBs) upon collision with replication forks, implying that DSB repair pathways could be involved in the processing/repair of Top1-mediated DNA damage. Here we report that Top1-mediated DNA damage is repaired primarily by homologous recombination, a major pathway of DSB repair. Unexpectedly, however, we found that nonhomologous end joining (NHEJ), another DSB repair pathway, has no positive role in the relevant repair; notably, DT40 cell mutants lacking either of the NHEJ factors (namely, Ku70, DNA-dependent protein kinase catalytic subunit, and DNA ligase IV) were resistant to killing by CPT. In addition, we showed that the absence of NHEJ alleviates the requirement of homologous recombination in the repair of CPT-induced DNA damage. Our results indicate that NHEJ can be a cytotoxic pathway in the presence of CPT, shedding new light on the molecular mechanisms for the formation and repair of Top1-mediated DNA damage in vertebrates. Thus, our data have significant implications for cancer chemotherapy involving Top1 inhibitors.

Received for publication, December 19, 2003 , and in revised form, May 17, 2004.

^* This work was supported by the Public Trust Haraguchi Memorial Cancer Research Fund, by grants from the Uehara Memorial Foundation, by grants from the Yamanouchi Foundation for Research on Metabolic Disorders, by grants from the Inamori Foundation, and by grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Kihara Inst. for Biological Research, Yokohama City University, Maioka-cho 641-12, Totsuka-ku, Yokohama 244-0813, Japan. Tel.: 81-45-820-1907; Fax: 81-45-820-1901; E-mail: nadachi{at}yokohama-cu.ac.jp.

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