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ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion

Author

Listed:
  • Demis Menolfi

    (Columbia University)

  • Brian J. Lee

    (Columbia University)

  • Hanwen Zhang

    (Columbia University)

  • Wenxia Jiang

    (Columbia University)

  • Nicole E. Bowen

    (Emory University School of Medicine)

  • Yunyue Wang

    (Columbia University)

  • Junfei Zhao

    (Columbia University)

  • Antony Holmes

    (Columbia University)

  • Steven Gershik

    (Columbia University)

  • Raul Rabadan

    (Columbia University)

  • Baek Kim

    (Emory University School of Medicine)

  • Shan Zha

    (Columbia University
    Columbia University
    Columbia University
    Columbia University)

Abstract

The ATR kinase, which coordinates cellular responses to DNA replication stress, is also essential for the proliferation of normal unstressed cells. Although its role in the replication stress response is well defined, the mechanisms by which ATR supports normal cell proliferation remain elusive. Here, we show that ATR is dispensable for the viability of G0-arrested naïve B cells. However, upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication and dNTP levels can be restored in Atr-deficient cells by suppressing origin firing, such as partial inhibition of CDC7 and CDK1 kinase activities. Together, these findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and importantly also other replication factors.

Suggested Citation

  • Demis Menolfi & Brian J. Lee & Hanwen Zhang & Wenxia Jiang & Nicole E. Bowen & Yunyue Wang & Junfei Zhao & Antony Holmes & Steven Gershik & Raul Rabadan & Baek Kim & Shan Zha, 2023. "ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39332-5
    DOI: 10.1038/s41467-023-39332-5
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