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Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but compromises the reactivation of stalled replication forks

Oncogene volume 23, pages 3872–3882 (2004)Cite this article

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant DNA end-sensing and binding molecule. Inactivation of PARP-1 by chemicals and genetic mutations slows cell proliferation, increases sister chromatid exchange (SCE), micronuclei formation and chromosome instability, and shortens telomeres. Given its affinity to DNA breaks and temporal occupation on DNA strand break sites, PARP-1 is proposed to prevent inappropriate DNA recombination. We investigated the potential role of PARP-1 in repair of DNA double-strand breaks (DSBs) and stalled replication forks. PARP-1−/− embryonic stem cells and embryonic fibroblast cells exhibited normal repair of DNA DSBs by either homologous recombination (HR) or nonhomologous end-joining (NHEJ) pathways. Inactivation of PARP-1 did not interfere with gene-targeting efficiency in ES cells. However, PARP-1−/− cells were hypersensitive to the replication damage agent hydroxyurea (HU)-induced cell death and exhibited enhanced SCE formation. Ablation of PARP-1 delayed reactivation of stalled replication forks imposed by HU and re-entry into the G2-M phase after HU release. These data indicate that PARP-1 is dispensable in HR induced by DSBs, but is involved in the repair and reactivation of stalled replication forks.

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Acknowledgements

We thank Dr S West for the Rad51 antibody. We also thank Ms Jocelyne Michelon for technical assistance and Drs Z Herceg, W-M Tong and E Van Dyck for critical reading of the manuscript. Y-G Yang and S Patnaik are supported by a postdoctoral fellowship from the International Agency for Research on Cancer (IARC). This study is supported by the Association pour la Recherche sur le Cancer (ARC), France and the Association for International Cancer Research (AICR), UK.

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Authors and Affiliations

  1. International Agency for Research on Cancer (IARC), 150 cours Albert-Thomas, Lyon, 69008, France

    Yun-Gui Yang, Ulrich Cortes, Srinivas Patnaik & Zhao-Qi Wang

  2. Memorial Sloan-Kettering Cancer Center, New York, 10021, NY, USA

    Maria Jasin

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  1. Yun-Gui Yang
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  2. Ulrich Cortes
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Correspondence to Zhao-Qi Wang.

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Yang, YG., Cortes, U., Patnaik, S. et al. Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but compromises the reactivation of stalled replication forks. Oncogene 23, 3872–3882 (2004). https://doi.org/10.1038/sj.onc.1207491

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