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HDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130

Author

Listed:
  • Anja Göder

    (University Medical Center Mainz)

  • Claudia Emmerich

    (Center for Molecular Biomedicine (CMB))

  • Teodora Nikolova

    (University Medical Center Mainz)

  • Nicole Kiweler

    (University Medical Center Mainz)

  • Maria Schreiber

    (Center for Molecular Biomedicine (CMB))

  • Toni Kühl

    (University of Bonn)

  • Diana Imhof

    (University of Bonn)

  • Markus Christmann

    (University Medical Center Mainz)

  • Thorsten Heinzel

    (Center for Molecular Biomedicine (CMB))

  • Günter Schneider

    (Technical University of Munich)

  • Oliver H. Krämer

    (University Medical Center Mainz)

Abstract

Checkpoint kinases sense replicative stress to prevent DNA damage. Here we show that the histone deacetylases HDAC1/HDAC2 sustain the phosphorylation of the checkpoint kinases ATM, CHK1 and CHK2, activity of the cell cycle gatekeeper kinases WEE1 and CDK1, and induction of the tumour suppressor p53 in response to stalled DNA replication. Consequently, HDAC inhibition upon replicative stress promotes mitotic catastrophe. Mechanistically, HDAC1 and HDAC2 suppress the expression of PPP2R3A/PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2 (PP2A). Genetic elimination of PR130 reveals that PR130 promotes dephosphorylation of ATM by PP2A. Moreover, the ablation of PR130 slows G1/S phase transition and increases the levels of phosphorylated CHK1, replication protein A foci and DNA damage upon replicative stress. Accordingly, stressed PR130 null cells are very susceptible to HDAC inhibition, which abrogates the S phase checkpoint, induces apoptosis and reduces the homologous recombination protein RAD51. Thus, PR130 controls cell fate decisions upon replicative stress.

Suggested Citation

  • Anja Göder & Claudia Emmerich & Teodora Nikolova & Nicole Kiweler & Maria Schreiber & Toni Kühl & Diana Imhof & Markus Christmann & Thorsten Heinzel & Günter Schneider & Oliver H. Krämer, 2018. "HDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03096-0
    DOI: 10.1038/s41467-018-03096-0
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