Abstract 2844: A cytosolic DNA/Ca2+-dependent signaling pathway for genome protection during replication stress

Abstract Protecting the replication fork structure, especially under replication stress, is essential for maintaining genome integrity and stability. Defects in fork protection, often linked to mutations in tumor suppressor genes like BRCA1, BRCA2 and FANCD2, can lead to genomic instability and consequently, cancer progression. Such defects may also influence cancer progression by altering the tumor microenvironment through the generation of cytosolic DNA fragments that activate the innate immune response. Intriguingly, our recent findings indicate that cytosolic DNA, produced after replication stress, unexpectedly also supports replication fork protection. This protective effect is mediated through a complex signaling pathway that involves the activation of the cGAS/cGAMP/STING axis, Ca2+ release from the endoplasmic reticulum via the TRPV2 ion channel, activation of CaMKK2 and AMPK protein kinases, and the inhibition of the EXO1 nuclease. Disruption of this pathway results in excessive fork processing, chromosomal instability and heightend sensitivity to replication stress inducers. The newly uncovered links between innate immune factors, intracellular Ca2+ and genome maintenance in this novel signaling pathway may open new avenues for cancer treatment. (Li et al., Mol Cell 2019, 74:1123-1137; Li, Kong et al., Mol Cell 2023, 85:556-573; Kong, Cheng et al., Nat Commun 2024, 15:4609) Citation Format: Zhongsheng You. A cytosolic DNA/Ca2+-dependent signaling pathway for genome protection during replication stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2844.