HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 279/36/37343    most recent M313910200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Adachi, N. Articles by Koyama, H. Search for Related Content PubMed PubMed Citation Articles by Adachi, N. Articles by Koyama, H. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Saberi, M. Nakahara, J. E. Sale, K. Kikuchi, H. Arakawa, J.-M. Buerstedde, K. Yamamoto, S. Takeda, and E. Sonoda The 9-1-1 DNA Clamp Is Required for Immunoglobulin Gene Conversion Mol. Cell. Biol., October 1, 2008; 28(19): 6113 - 6122. [Abstract] [Full Text] [PDF]

				Y. Murakawa, E. Sonoda, L. J. Barber, W. Zeng, K. Yokomori, H. Kimura, A. Niimi, A. Lehmann, G. Y. Zhao, H. Hochegger, et al. Inhibitors of the Proteasome Suppress Homologous DNA Recombination in Mammalian Cells Cancer Res., September 15, 2007; 67(18): 8536 - 8543. [Abstract] [Full Text] [PDF]

				F. Karimi-Busheri, A. Rasouli-Nia, J. Allalunis-Turner, and M. Weinfeld Human Polynucleotide Kinase Participates in Repair of DNA Double-Strand Breaks by Nonhomologous End Joining but not Homologous Recombination Cancer Res., July 15, 2007; 67(14): 6619 - 6625. [Abstract] [Full Text] [PDF]

				M. Kohzaki, A. Hatanaka, E. Sonoda, M. Yamazoe, K. Kikuchi, N. Vu Trung, D. Szuts, J. E. Sale, H. Shinagawa, M. Watanabe, et al. Cooperative Roles of Vertebrate Fbh1 and Blm DNA Helicases in Avoidance of Crossovers during Recombination Initiated by Replication Fork Collapse Mol. Cell. Biol., April 15, 2007; 27(8): 2812 - 2820. [Abstract] [Full Text] [PDF]

				A. Saberi, H. Hochegger, D. Szuts, L. Lan, A. Yasui, J. E. Sale, Y. Taniguchi, Y. Murakawa, W. Zeng, K. Yokomori, et al. RAD18 and Poly(ADP-Ribose) Polymerase Independently Suppress the Access of Nonhomologous End Joining to Double-Strand Breaks and Facilitate Homologous Recombination-Mediated Repair Mol. Cell. Biol., April 1, 2007; 27(7): 2562 - 2571. [Abstract] [Full Text] [PDF]

				M. Valencia-Burton, M. Oki, J. Johnson, T. A. Seier, R. Kamakaka, and J. E. Haber Different Mating-Type-Regulated Genes Affect the DNA Repair Defects of Saccharomyces RAD51, RAD52 and RAD55 Mutants Genetics, September 1, 2006; 174(1): 41 - 55. [Abstract] [Full Text] [PDF]

				J.-P. Capp, F. Boudsocq, P. Bertrand, A. Laroche-Clary, P. Pourquier, B. S. Lopez, C. Cazaux, J.-S. Hoffmann, and Y. Canitrot The DNA polymerase {lambda} is required for the repair of non-compatible DNA double strand breaks by NHEJ in mammalian cells Nucleic Acids Res., May 31, 2006; 34(10): 2998 - 3007. [Abstract] [Full Text] [PDF]

				S.-J. Shih, T. Erbele, and A. Y. Chen Ku86 Modulates DNA Topoisomerase I-Mediated Radiosensitization, but not Cytotoxicity, in Mammalian Cells Cancer Res., October 15, 2005; 65(20): 9194 - 9199. [Abstract] [Full Text] [PDF]

				Y. Yonetani, H. Hochegger, E. Sonoda, S. Shinya, H. Yoshikawa, S. Takeda, and M. Yamazoe Differential and collaborative actions of Rad51 paralog proteins in cellular response to DNA damage Nucleic Acids Res., August 10, 2005; 33(14): 4544 - 4552. [Abstract] [Full Text] [PDF]

				S. So, N. Adachi, M. R. Lieber, and H. Koyama Genetic Interactions between BLM and DNA Ligase IV in Human Cells J. Biol. Chem., December 31, 2004; 279(53): 55433 - 55442. [Abstract] [Full Text] [PDF]