Polβ modulates the expression of type I interferon via STING pathway.

Abstract

DNA Polymerase β (Polβ) is a key enzyme in base excision repair (BER), which is very important in maintaining the stability and integrity of the genome. Mutant Polβ is closely associated with carcinogenesis. However, Polβ is highly expressed in most cancers, but the underlying mechanism is not well understood. Here, we found that breast cancer cells MCF-7 with Polβ knockdown exhibited high levels of type I interferon and were easily eliminated by natural killer (NK) cells.Similarly, Polβ-mutant (R137Q) mice exhibited chronic inflammation symptoms in multiple organs and upregulated type I interferon levels. Further results showed that Polβ deficiency caused more DNA damage accumulation in cells and triggered the leakage of damaged DNA into the cytoplasm, which activated the STING/IRF3 pathway, promoted phosphorylated IRF3 translocating into the nucleus and enhanced the expression of type I interferon and proinflammatory cytokines. In addition, this effect could be eliminated by Polβ overexpression, STING inhibitor or STING knockdown. Taken together, our findings provide mechanistic insight into the role of Polβ in cancers by linking DNA repair and the inflammatory STING pathway.

• Authors: Miaoling Huang, Ting Wu, Rui Liu, Meina Wang, Munan Shi, Jingyu Xin, Shan Shao, Xingqi Zhao, Ying Ma, Lili Gu, Zhigang Guo, Feiyan Pan
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 621 Pg. 137-143 (09 17 2022) ISSN: 1090-2104 [Electronic] United States
• PMID: 35834922 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Interferon Type I
• Membrane Proteins
• Sting1 protein, mouse
• DNA Polymerase beta

Topics

• Animals
• DNA Damage
• DNA Polymerase beta (metabolism)
• DNA Repair
• Interferon Type I
• Membrane Proteins (metabolism)
• Mice