Polβ modulates the expression of type I interferon via STING pathway

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.