2. Academic Validation
  3. STING directly interacts with PAR to promote apoptosis upon acute ionizing radiation-mediated DNA damage

STING directly interacts with PAR to promote apoptosis upon acute ionizing radiation-mediated DNA damage

  • Cell Death Differ. 2025 Feb 12. doi: 10.1038/s41418-025-01457-z.
Yirong Sun # 1 2,  Saba R Aliyari # 3,  Kislay Parvatiyar 3 4,  Lulan Wang 3,  Anjie Zhen 3,  Wei Sun 5,  Xiaobo Han 5,  Adele Zhang 3,  Ethan Kato 3,  Helen Shi 3,  Elena De Schutter 3,  William H McBride 6,  Samuel W French 7,  Genhong Cheng 8
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. sun_yirong@gibh.ac.cn.
  • 2 Department of Microbiology, Immunology and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA, USA. sun_yirong@gibh.ac.cn.
  • 3 Department of Microbiology, Immunology and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA, USA.
  • 4 Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, LA, USA.
  • 5 CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  • 6 Department of Radiation Oncology, University of California-Los Angeles, Los Angeles, CA, USA.
  • 7 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • 8 Department of Microbiology, Immunology and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA, USA. gcheng@mednet.ucla.edu.
  • # Contributed equally.
PMID: 39939798 DOI: 10.1038/s41418-025-01457-z
Abstract

Acute ionizing radiation (IR) causes severe DNA damage, leading to cell cycle arrest, cell death, and activation of the innate immune system. The role and signaling pathway of stimulator of interferon genes (STING) in IR-induced tissue damage and cell death are not well understood. This study revealed that STING is crucial for promoting Apoptosis in response to DNA damage caused by acute IR both in vitro and in vivo. STING binds to poly (ADP‒ribose) (PAR) produced by activated poly (ADP‒ribose) polymerase-1 (PARP1) upon IR. Compared with that in WT cells, Apoptosis was suppressed in STINGgt-/gt- cells. Excessive PAR production by PARP1 due to DNA damage enhances STING phosphorylation, and inhibiting PARP1 reduces cell Apoptosis after IR. In vivo, IR-induced crypt cell death was significantly lower in STINGgt-/gt- mice or with low-dose PARP1 Inhibitor, PJ34, resulting in substantial resistance to abdominal irradiation. STING deficiency or inhibition of PARP1 function can reduce the expression of the proapoptotic gene PUMA, decrease the localization of Bax on the mitochondrial membrane, and thus reduce cell Apoptosis. Our findings highlight crucial roles for STING and PAR in the IR-mediated induction of Apoptosis, which may have therapeutic implications for controlling radiation-induced Apoptosis or acute radiation symptoms. STING responds to acute ionizing radiation-mediated DNA damage by directly binding to poly (ADP-ribose) (PAR) produced by activated poly (ADP-ribose) polymerase-1 (PARP1), and mainly induces cell Apoptosis through Puma-Bax interaction. STING deficiency or reduced production of PAR protected mice against Acute Radiation Syndrome.

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