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

Demis Menolfi, Brian J. Lee, Hanwen Zhang, Wenxia Jiang, Nicole E. Bowen, Yunyue Wang, Junfei Zhao, Antony Holmes, Steven Gershik, Raul Rabadan, Baek Kim and Shan Zha ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39332-5

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