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TCAF1 promotes TRPV2-mediated Ca2+ release in response to cytosolic DNA to protect stressed replication forks

Author

Listed:
  • Lingzhen Kong

    (Washington University School of Medicine)

  • Chen Cheng

    (Washington University School of Medicine)

  • Abigael Cheruiyot

    (Washington University School of Medicine)

  • Jiayi Yuan

    (Washington University School of Medicine)

  • Yichan Yang

    (Washington University School of Medicine)

  • Sydney Hwang

    (Washington University School of Medicine)

  • Daniel Foust

    (Washington University School of Medicine)

  • Ning Tsao

    (Washington University in St. Louis School of Medicine)

  • Emily Wilkerson

    (Washington University School of Medicine)

  • Nima Mosammaparast

    (Washington University in St. Louis School of Medicine)

  • Michael B. Major

    (Washington University School of Medicine)

  • David W. Piston

    (Washington University School of Medicine)

  • Shan Li

    (Washington University School of Medicine
    Zhejiang University School of Medicine
    Zhejiang University)

  • Zhongsheng You

    (Washington University School of Medicine)

Abstract

The protection of the replication fork structure under stress conditions is essential for genome maintenance and cancer prevention. A key signaling pathway for fork protection involves TRPV2-mediated Ca2+ release from the ER, which is triggered after the generation of cytosolic DNA and the activation of cGAS/STING. This results in CaMKK2/AMPK activation and subsequent Exo1 phosphorylation, which prevent aberrant fork processing, thereby ensuring genome stability. However, it remains poorly understood how the TRPV2 channel is activated by the presence of cytosolic DNA. Here, through a genome-wide CRISPR-based screen, we identify TRPM8 channel-associated factor 1 (TCAF1) as a key factor promoting TRPV2-mediated Ca2+ release under replication stress or other conditions that activate cGAS/STING. Mechanistically, TCAF1 assists Ca2+ release by facilitating the dissociation of STING from TRPV2, thereby relieving TRPV2 repression. Consistent with this function, TCAF1 is required for fork protection, chromosomal stability, and cell survival after replication stress.

Suggested Citation

  • Lingzhen Kong & Chen Cheng & Abigael Cheruiyot & Jiayi Yuan & Yichan Yang & Sydney Hwang & Daniel Foust & Ning Tsao & Emily Wilkerson & Nima Mosammaparast & Michael B. Major & David W. Piston & Shan L, 2024. "TCAF1 promotes TRPV2-mediated Ca2+ release in response to cytosolic DNA to protect stressed replication forks," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48988-6
    DOI: 10.1038/s41467-024-48988-6
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    References listed on IDEAS

    as
    1. Andrea Ablasser & Marion Goldeck & Taner Cavlar & Tobias Deimling & Gregor Witte & Ingo Röhl & Karl-Peter Hopfner & Janos Ludwig & Veit Hornung, 2013. "cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING," Nature, Nature, vol. 498(7454), pages 380-384, June.
    2. PingHsun Hsieh & Vy Dang & Mitchell R. Vollger & Yafei Mao & Tzu-Hsueh Huang & Philip C. Dishuck & Carl Baker & Stuart Cantsilieris & Alexandra P. Lewis & Katherine M. Munson & Melanie Sorensen & Anne, 2021. "Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    3. Ashna Dhoonmoon & Claudia M. Nicolae & George-Lucian Moldovan, 2022. "The KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
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