Published online
doi:10.1083/jcb.200806068
The Journal of Cell Biology, Vol. 183, No. 7, 1203-1212
The Rockefeller University Press, 0021-9525 $30.00
© Sugimura et al.
PARP-1 ensures regulation of replication fork progression by homologous recombination on damaged DNA
Kazuto Sugimura1,
Shin-ichiro Takebayashi2,
Hiroshi Taguchi1,
Shunichi Takeda3, and
Katsuzumi Okumura1
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
Correspondence to Kazuto Sugimura: sugimura{at}bio.mie-u.ac.jp; or Katsuzumi Okumura: katsu{at}bio.mie-u.ac.jp
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.
Abbreviations used in this paper: CPT, camptothecin; DSB, double-strand break; EYFP, enhanced YFP; HR, homologous recombination; NHEJ, nonhomologous end joining; PARP, poly-ADP ribose polymerase; PCNA, proliferating cell nuclear antigen; SSB, single-strand break; SSBR, SSB repair; Topo I, topoisomerase I.
© 2008 Sugimura et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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