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Molecular and Cellular Biology, April 2007, p. 2562-2571, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01243-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

RAD18 and Poly(ADP-Ribose) Polymerase Independently Suppress the Access of Nonhomologous End Joining to Double-Strand Breaks and Facilitate Homologous Recombination-Mediated Repair{triangledown} ,{dagger}

Alihossein Saberi,1 Helfrid Hochegger,1 David Szuts,2 Li Lan,3 Akira Yasui,3 Julian E. Sale,2 Yoshihito Taniguchi,1 Yasuhiro Murakawa,1 Weihua Zeng,4 Kyoko Yokomori,4 Thomas Helleday,5 Hirobumi Teraoka,6 Hiroshi Arakawa,7 Jean-Marie Buerstedde,7 and Shunichi Takeda1*

CREST Research Project, Radiation Genetics, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan,1 Medical Research Council, Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Hill Roads, Cambridge CB2 2QH, United Kingdom,2 Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan,3 Biological Chemistry Department, School of Medicine, University of California, Irvine, California 92697-1700,4 Department of Genetics, Microbiology and Toxicology, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden,5 Department of Pathologic Biochemistry, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan,6 Institute of Molecular Radiobiology, GSF, Neuherberg, Germany7

Received 8 July 2006/ Returned for modification 7 August 2006/ Accepted 17 November 2006

The Saccharomyces cerevisiae RAD18 gene is essential for postreplication repair but is not required for homologous recombination (HR), which is the major double-strand break (DSB) repair pathway in yeast. Accordingly, yeast rad18 mutants are tolerant of camptothecin (CPT), a topoisomerase I inhibitor, which induces DSBs by blocking replication. Surprisingly, mammalian cells and chicken DT40 cells deficient in Rad18 display reduced HR-dependent repair and are hypersensitive to CPT. Deletion of nonhomologous end joining (NHEJ), a major DSB repair pathway in vertebrates, in rad18-deficient DT40 cells completely restored HR-mediated DSB repair, suggesting that vertebrate Rad18 regulates the balance between NHEJ and HR. We previously reported that loss of NHEJ normalized the CPT sensitivity of cells deficient in poly(ADP-ribose) polymerase 1 (PARP1). Concomitant deletion of Rad18 and PARP1 synergistically increased CPT sensitivity, and additional inactivation of NHEJ normalized this hypersensitivity, indicating their parallel actions. In conclusion, higher-eukaryotic cells separately employ PARP1 and Rad18 to suppress the toxic effects of NHEJ during the HR reaction at stalled replication forks.

* Corresponding author. Mailing address: CREST Research Project, Radiation Genetics, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81-75-753-4411. Fax: 81-75-753-4419. E-mail: stakeda{at}rg.med.kyoto-u.ac.jp.

{triangledown} Published ahead of print on 22 January 2007.

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

Molecular and Cellular Biology, April 2007, p. 2562-2571, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01243-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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