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CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection

Author

Listed:
  • Rishi Kumar Jaiswal

    (Loyola University Chicago Stritch School of Medicine)

  • Kai-Hang Lei

    (National Taiwan University)

  • Megan Chastain

    (Washington State University)

  • Yuan Wang

    (Rutgers Cancer Institute of New Jersey)

  • Olga Shiva

    (Washington State University)

  • Shan Li

    (Washington University School of Medicine)

  • Zhongsheng You

    (Washington University School of Medicine)

  • Peter Chi

    (National Taiwan University
    Academia Sinica)

  • Weihang Chai

    (Loyola University Chicago Stritch School of Medicine)

Abstract

Keeping replication fork stable is essential for safeguarding genome integrity; hence, its protection is highly regulated. The CTC1-STN1-TEN1 (CST) complex protects stalled forks from aberrant MRE11-mediated nascent strand DNA degradation (NSD). However, the activation mechanism for CST at forks is unknown. Here, we report that STN1 is phosphorylated in its intrinsic disordered region. Loss of STN1 phosphorylation reduces the replication stress-induced STN1 localization to stalled forks, elevates NSD, increases MRE11 access to stalled forks, and decreases RAD51 localization at forks, leading to increased genome instability under perturbed DNA replication condition. STN1 is phosphorylated by both the ATR-CHK1 and the calcium-sensing kinase CaMKK2 in response to hydroxyurea/aphidicolin treatment or elevated cytosolic calcium concentration. Cancer-associated STN1 variants impair STN1 phosphorylation, conferring inability of fork protection. Collectively, our study uncovers that CaMKK2 and ATR-CHK1 target STN1 to enable its fork protective function, and suggests an important role of STN1 phosphorylation in cancer development.

Suggested Citation

  • Rishi Kumar Jaiswal & Kai-Hang Lei & Megan Chastain & Yuan Wang & Olga Shiva & Shan Li & Zhongsheng You & Peter Chi & Weihang Chai, 2023. "CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43685-2
    DOI: 10.1038/s41467-023-43685-2
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