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FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

Author

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  • Kasper Fugger

    (Biotech Research and Innovation Centre (BRIC), University of Copenhagen)

  • Wai Kit Chu

    (Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
    Nordea Center for Healthy Aging, University of Copenhagen, Panum Institute)

  • Peter Haahr

    (Biotech Research and Innovation Centre (BRIC), University of Copenhagen)

  • Arne Nedergaard Kousholt

    (Biotech Research and Innovation Centre (BRIC), University of Copenhagen)

  • Halfdan Beck

    (Biotech Research and Innovation Centre (BRIC), University of Copenhagen)

  • Miranda J. Payne

    (Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital)

  • Katsuhiro Hanada

    (Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital)

  • Ian D. Hickson

    (Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital
    Nordea Center for Healthy Aging, University of Copenhagen, Panum Institute)

  • Claus Storgaard Sørensen

    (Biotech Research and Innovation Centre (BRIC), University of Copenhagen)

Abstract

The molecular events occurring following the disruption of DNA replication forks are poorly characterized, despite extensive use of replication inhibitors such as hydroxyurea in the treatment of malignancies. Here, we identify a key role for the FBH1 helicase in mediating DNA double-strand break formation following replication inhibition. We show that FBH1-deficient cells are resistant to killing by hydroxyurea, and exhibit impaired activation of the pro-apoptotic factor p53, consistent with decreased DNA double-strand break formation. Similar findings were obtained in murine ES cells carrying disrupted alleles of Fbh1. We also show that FBH1 through its helicase activity co-operates with the MUS81 nuclease in promoting the endonucleolytic DNA cleavage following prolonged replication stress. Accordingly, MUS81 and EME1-depleted cells show increased resistance to the cytotoxic effects of replication stress. Our data suggest that FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA double-strand breaks.

Suggested Citation

  • Kasper Fugger & Wai Kit Chu & Peter Haahr & Arne Nedergaard Kousholt & Halfdan Beck & Miranda J. Payne & Katsuhiro Hanada & Ian D. Hickson & Claus Storgaard Sørensen, 2013. "FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress," Nature Communications, Nature, vol. 4(1), pages 1-8, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2395
    DOI: 10.1038/ncomms2395
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