Article
- The EMBO Journal (2006) 25, 1305 - 1314
- doi:10.1038/sj.emboj.7601015
Published online: 23 February 2006
Subject Category:
Parp-1 protects homologous recombination from interference by Ku and Ligase IV in vertebrate cells
Helfrid Hochegger1, Donniphat Dejsuphong1, Toru Fukushima1, Ciaran Morrison2, Eiichiro Sonoda1, Valérie Schreiber3, Guang Yu Zhao1, Alihossein Saberi1, Mitsuko Masutani4, Noritaka Adachi5, Hideki Koyama5, Gilbert de Murcia3 and Shunichi Takeda1
- Crest Laboratory, Department of Radiation Genetics, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
- Department of Biochemistry and NCBES, National University of Ireland-Galway, Ireland
- Département Intégrité du génome de l'UMR7175 du CNRS, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, Illkirch, France
- ADP-ribosylation in Oncology Project, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
- Kihara Institute for Biological Research, Yokohama City University, Totsuka-ku, Yokohama, Japan
Correspondence to:
Shunichi Takeda, Crest Laboratory, Department of Radiation Genetics, Faculty of Medicine, Kyoto University; Sakyo-ku, 606-8501 Kyoto, Japan. Tel.: +81 75 753 4410; Fax: +81 75 753 4419; E-mail: stakeda@rg.med.kyoto-u.ac.jp
Received 27 July 2005; Accepted 30 January 2006
Abstract
Parp-1 and Parp-2 are activated by DNA breaks and have been implicated in the repair of DNA single-strand breaks (SSB). Their involvement in double-strand break (DSB) repair mediated by homologous recombination (HR) or nonhomologous end joining (NHEJ) remains unclear. We addressed this question using chicken DT40 cells, which have the advantage of carrying only a PARP-1 gene but not a PARP-2 gene. We found that PARP-1-/- DT40 mutants show reduced levels of HR and are sensitive to various DSB-inducing genotoxic agents. Surprisingly, this phenotype was strictly dependent on the presence of Ku, a DSB-binding factor that mediates NHEJ. PARP-1/KU70 double mutants were proficient in the execution of HR and displayed elevated resistance to DSB-inducing drugs. Moreover, we found deletion of Ligase IV, another NHEJ gene, suppressed the camptothecin of PARP-1-/- cells. Our results suggest a new critical function for Parp in minimizing the suppressive effects of Ku and the NHEJ pathway on HR.
Keywords:
- base excision repair,
- camptothecin,
- homologous recombination,
- ionizing radiation,
- MMS
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