2. Academic Validation
  3. Cytosolic DNA sensing by cGAS/STING promotes TRPV2-mediated Ca2+ release to protect stressed replication forks

Cytosolic DNA sensing by cGAS/STING promotes TRPV2-mediated Ca2+ release to protect stressed replication forks

  • Mol Cell. 2023 Jan 14;S1097-2765(22)01217-5. doi: 10.1016/j.molcel.2022.12.034.
Shan Li 1,  Lingzhen Kong 2,  Ying Meng 3,  Chen Cheng 2,  Delphine Sangotokun Lemacon 2,  Zheng Yang 2,  Ke Tan 2,  Abigael Cheruiyot 2,  Zhimin Lu 3,  Zhongsheng You 4
Affiliations

Affiliations

  • 1 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
  • 2 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 3 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
  • 4 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: zyou@wustl.edu.
PMID: 36696898 DOI: 10.1016/j.molcel.2022.12.034
Abstract

The protection of DNA replication forks under stress is essential for genome maintenance and Cancer suppression. One mechanism of fork protection involves an elevation in intracellular CA2+ ([CA2+]i), which in turn activates CaMKK2 and AMPK to prevent uncontrolled fork processing by Exo1. How replication stress triggers [CA2+]i elevation is unclear. Here, we report a role of cytosolic self-DNA (cytosDNA) and the ion channel TRPV2 in [CA2+]i induction and fork protection. Replication stress leads to the generation of ssDNA and dsDNA species that, upon translocation into cytoplasm, trigger the activation of the sensor protein cGAS and the production of cGAMP. The subsequent binding of cGAMP to STING causes its dissociation from TRPV2, leading to TRPV2 derepression and CA2+ release from the ER, which in turn activates the downstream signaling cascade to prevent fork degradation. This CA2+-dependent genome protection pathway is also activated in response to replication stress caused by oncogene activation.

Keywords

AMPK; CaMKK2; STING; TREX1; TRPV2; cGAS; cytosolic DNA; fork resection; intracellular Ca(2+); replication stress.

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