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Molecular and Cellular Biology, August 2005, p. 6948-6955, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.6948-6955.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Fen-1 Facilitates Homologous Recombination by Removing Divergent Sequences at DNA Break Ends{dagger}

Koji Kikuchi,1,2 Yoshihito Taniguchi,1,2 Atsushi Hatanaka,1 Eiichiro Sonoda,1,2 Helfrid Hochegger,1 Noritaka Adachi,3 Yasuo Matsuzaki,3 Hideki Koyama,3 Dik C. van Gent,4 Maria Jasin,5 and Shunichi Takeda1,2*

Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto 606-8501, Japan,1 CREST, JST (Japan Science and Technology), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan,2 Kihara Institute for Biological Research, Yokohama City University, Maioka-cho 641-12, Totsuka-ku, Yokohama 244-0813, Japan,3 Department of Cell Biology and Genetics, Erasmus Medical Center, P.O. Box 1738, 3000, DR Rotterdam, The Netherlands,4 Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 100215

Received 21 February 2005/ Returned for modification 5 April 2005/ Accepted 27 May 2005

Homologous recombination (HR) requires nuclease activities at multiple steps, but the contribution of individual nucleases to the processing of double-strand DNA ends at different stages of HR has not been clearly defined. We used chicken DT40 cells to investigate the role of flap endonuclease 1 (Fen-1) in HR. FEN-1-deficient cells exhibited a significant decrease in the efficiency of immunoglobulin gene conversion while being proficient in recombination between sister chromatids, suggesting that Fen-1 may play a role in HR between sequences of considerable divergence. To clarify whether sequence divergence at DNA ends is truly the reason for the observed HR defect in FEN-1–/– cells we inserted a unique I-SceI restriction site in the genome and tested various donor and recipient HR substrates. We found that the efficiency of HR-mediated DNA repair was indeed greatly diminished when divergent sequences were present at the DNA break site. We conclude that Fen-1 eliminates heterologous sequences at DNA damage site and facilitates DNA repair by HR.

* Corresponding author. Mailing address: Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81-75-753-4410. Fax: 81-75-753-4419. E-mail: stakeda{at}rg.med.kyoto-u.ac.jp.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2005, p. 6948-6955, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.6948-6955.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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