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ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1

Author

Listed:
  • Tatiana Moiseeva

    (University of Pittsburgh School of Medicine, Hillman Cancer Center)

  • Brian Hood

    (Inova Schar Cancer Institute, Inova Center for Personalized Health)

  • Sandy Schamus

    (University of Pittsburgh School of Medicine, Hillman Cancer Center)

  • Mark J. O’Connor

    (DNA Damage Response Biology, Innovative Medicines and Early Clinical Development)

  • Thomas P. Conrads

    (Inova Schar Cancer Institute, Inova Center for Personalized Health)

  • Christopher J. Bakkenist

    (University of Pittsburgh School of Medicine, Hillman Cancer Center
    University of Pittsburgh)

Abstract

ATR kinase activity slows replication forks and prevents origin firing in damaged cells. Here we describe proteomic analyses that identified mechanisms through which ATR kinase inhibitors induce unscheduled origin firing in undamaged cells. ATR-Chk1 inhibitor-induced origin firing is mediated by Cdc7 kinase through previously undescribed phosphorylations on GINS that induce an association between GINS and And-1. ATR-Chk1 inhibitor-induced origin firing is blocked by prior exposure to DNA damaging agents showing that the prevention of origin firing does not require ongoing ATR activity. In contrast, ATR-Chk1 inhibitor-induced origins generate additional replication forks that are targeted by subsequent exposure to DNA damaging agents. Thus, the sequence of administration of an ATR kinase inhibitor and a DNA damaging agent impacts the DNA damage induced by the combination. Our experiments identify competing ATR and Cdc7 kinase-dependent mechanisms at replication origins in human cells.

Suggested Citation

  • Tatiana Moiseeva & Brian Hood & Sandy Schamus & Mark J. O’Connor & Thomas P. Conrads & Christopher J. Bakkenist, 2017. "ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01401-x
    DOI: 10.1038/s41467-017-01401-x
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