Inflammatory kinase TBK1 suppresses homologous recombination DNA repair to sensitize tumors to chemotherapy.
TL;DR
Findings reveal a previously unrecognized function of TBK1 in modulating the DNA-damage response, linking inflammatory signaling to genome destabilization and identifying the TBK1-MRE11 axis as a potential target to enhance chemotherapeutic efficacy are revealed.
Abstract
Inflammation exerts context-dependent influences on tumor progression and therapeutic response. Although chemotherapy remains a cornerstone of cancer treatment, its functional interplay with inflammatory signaling is still incompletely understood. Here, we identify TANK-binding kinase 1 (TBK1) as a critical modulator of chemotherapeutic efficacy through its impact on DNA damage repair. TBK1 activation potentiates cancer-cell death induced by chemotherapeutic agents by promoting DNA damage and impairing homologous recombination (HR) repair. This effect occurs independently of canonical inflammatory cytokines, as demonstrated in IRF3- and p65- double deficient cells. Mechanistically, TBK1 suppresses recruitment of the key HR factor Meiotic Recombination 11 Homolog 1 (MRE11) to PARP1 at DNA-damage sites in a kinase-activity-dependent yet cytokine-independent manner. Furthermore, TBK1 activation correlates with enhanced p53 signaling and genomic instability, providing a molecular basis for its pro-death effects under chemotherapy. Collectively, these findings reveal a previously unrecognized function of TBK1 in modulating the DNA-damage response, linking inflammatory signaling to genome destabilization and identifying the TBK1-MRE11 axis as a potential target to enhance chemotherapeutic efficacy.