Polβ modulates the expression of type I interferon via STING pathway

Area of Science:

• Molecular Biology
• Cancer Research
• Immunology

Background:

• DNA Polymerase β (Polβ) is crucial for genome stability via base excision repair (BER).
• Polβ mutations are linked to cancer, and its high expression in tumors suggests a complex role.
• The mechanism behind Polβ's involvement in cancer, particularly its high expression, remains unclear.

Purpose of the Study:

• To investigate the role of Polβ in cancer development and the immune response.
• To elucidate the molecular mechanisms linking Polβ, DNA damage, and inflammation in cancer cells.
• To explore the potential of targeting the STING pathway in Polβ-related cancers.

Main Methods:

• Utilized Polβ knockdown in MCF-7 breast cancer cells.
• Examined Polβ-mutant (R137Q) mice to assess in vivo effects.
• Analyzed DNA damage, cytoplasmic DNA leakage, and the STING/IRF3 signaling pathway activation.
• Investigated the impact of Polβ overexpression, STING inhibition, and STING knockdown.

Main Results:

• Polβ knockdown in breast cancer cells led to increased type I interferon and NK cell sensitivity.
• Polβ-mutant mice showed chronic inflammation and elevated type I interferon levels.
• Polβ deficiency resulted in DNA damage accumulation, cytoplasmic DNA release, and STING/IRF3 pathway activation, boosting type I interferon and inflammatory cytokine production.
• These inflammatory effects were reversible with Polβ re-expression or STING pathway inhibition.

Conclusions:

• Polβ deficiency triggers an inflammatory response via the STING pathway due to cytoplasmic DNA leakage.
• This study links DNA repair mechanisms (Polβ) with innate immune signaling (STING) in the context of cancer.
• Findings offer mechanistic insights into Polβ's role in cancer and suggest therapeutic potential targeting the STING pathway.