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Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation

Author

Listed:
  • WooKee Min

    (Leibniz Institute For Age Research-Fritz Lipmann Institute (FLI))

  • Christopher Bruhn

    (Leibniz Institute For Age Research-Fritz Lipmann Institute (FLI))

  • Paulius Grigaravicius

    (Leibniz Institute For Age Research-Fritz Lipmann Institute (FLI)
    Present address: German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany)

  • Zhong-Wei Zhou

    (Leibniz Institute For Age Research-Fritz Lipmann Institute (FLI))

  • Fu Li

    (Leibniz Institute For Age Research-Fritz Lipmann Institute (FLI))

  • Anja Krüger

    (Leibniz Institute For Age Research-Fritz Lipmann Institute (FLI))

  • Bénazir Siddeek

    (Leibniz Institute For Age Research-Fritz Lipmann Institute (FLI))

  • Karl-Otto Greulich

    (Leibniz Institute For Age Research-Fritz Lipmann Institute (FLI)
    Faculty of Biology and Pharmacy, Friedrich-Schiller-University Jena)

  • Oliver Popp

    (University of Konstanz)

  • Chris Meisezahl

    (Leibniz Institute For Age Research-Fritz Lipmann Institute (FLI))

  • Cornelis F. Calkhoven

    (Leibniz Institute For Age Research-Fritz Lipmann Institute (FLI))

  • Alexander Bürkle

    (University of Konstanz)

  • Xingzhi Xu

    (Beijing Key Laboratory of DNA Damage Response, Capital Normal University)

  • Zhao-Qi Wang

    (Leibniz Institute For Age Research-Fritz Lipmann Institute (FLI)
    Faculty of Biology and Pharmacy, Friedrich-Schiller-University Jena)

Abstract

Damaged replication forks activate poly(ADP-ribose) polymerase 1 (PARP1), which catalyses poly(ADP-ribose) (PAR) formation; however, how PARP1 or poly(ADP-ribosyl)ation is involved in the S-phase checkpoint is unknown. Here we show that PAR, supplied by PARP1, interacts with Chk1 via a novel PAR-binding regulatory (PbR) motif in Chk1, independent of ATR and its activity. iPOND studies reveal that Chk1 associates readily with the unperturbed replication fork and that PAR is required for efficient retention of Chk1 and phosphorylated Chk1 at the fork. A PbR mutation, which disrupts PAR binding, but not the interaction with its partners Claspin or BRCA1, impairs Chk1 and the S-phase checkpoint activation, and mirrors Chk1 knockdown-induced hypersensitivity to fork poisoning. We find that long chains, but not short chains, of PAR stimulate Chk1 kinase activity. Collectively, we disclose a previously unrecognized mechanism of the S-phase checkpoint by PAR metabolism that modulates Chk1 activity at the replication fork.

Suggested Citation

  • WooKee Min & Christopher Bruhn & Paulius Grigaravicius & Zhong-Wei Zhou & Fu Li & Anja Krüger & Bénazir Siddeek & Karl-Otto Greulich & Oliver Popp & Chris Meisezahl & Cornelis F. Calkhoven & Alexander, 2013. "Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation," Nature Communications, Nature, vol. 4(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3993
    DOI: 10.1038/ncomms3993
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