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

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 Li () and Zhongsheng You ()
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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
Zhongsheng You: Washington University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48988-6

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