PARP-1 ensures regulation of replication fork progression by homologous recombination on damaged DNA |
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| Authors: | Kazuto Sugimura Shin-ichiro Takebayashi Hiroshi Taguchi Shunichi Takeda Katsuzumi Okumura |
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| Affiliation: | 1.Department of Life Science, Graduate School of Bioresources, Mie University, Tsu, Mie 514-8507, Japan;2.Department of Biological Science, Florida State University, Tallahassee, FL 32306;3.CREST Laboratory, Department of Radiation Genetics, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan |
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| Abstract: | Poly-ADP ribose polymerase 1 (PARP-1) is activated by DNA damage and has been implicated in the repair of single-strand breaks (SSBs). Involvement of PARP-1 in other DNA damage responses remains controversial. In this study, we show that PARP-1 is required for replication fork slowing on damaged DNA. Fork progression in PARP-1−/− DT40 cells is not slowed down even in the presence of DNA damage induced by the topoisomerase I inhibitor camptothecin (CPT). Mammalian cells treated with a PARP inhibitor or PARP-1–specific small interfering RNAs show similar results. The expression of human PARP-1 restores fork slowing in PARP-1−/− DT40 cells. PARP-1 affects SSB repair, homologous recombination (HR), and nonhomologous end joining; therefore, we analyzed the effect of CPT on DT40 clones deficient in these pathways. We find that fork slowing is correlated with the proficiency of HR-mediated repair. Our data support the presence of a novel checkpoint pathway in which the initiation of HR but not DNA damage delays the fork progression. |
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