Parp-1 protects homologous recombination from interference by Ku and Ligase IV in vertebrate cells |
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Authors: | Hochegger Helfrid Dejsuphong Donniphat Fukushima Toru Morrison Ciaran Sonoda Eiichiro Schreiber Valérie Zhao Guang Yu Saberi Alihossein Masutani Mitsuko Adachi Noritaka Koyama Hideki de Murcia Gilbert Takeda Shunichi |
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Institution: | Department of Radiation Genetics, Faculty of Medicine, Kyoto University, Kyoto, Japan. |
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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. |
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