Evidence of inter-tissue differences in the DNA damage response and the pro-oncogenic role of NF{kappa}B in mice with disengaged BRCA1-PALB2 interaction

The BRCA1-PALB2-BRCA2 axis plays an essential role in DNA homologous recombination repair (HRR), defect in which drives genome instability and cancer development. How cells with defects in this pathway respond to DNA damage in vivo and how tumors develop from these cells remain poorly defined. Here we analyzed several aspects of the DNA damage response in multiple tissues of Palb2 mutant mice in which the interaction between PALB2 and BRCA1 is disengaged. Without any challenge, the mutant mice showed increased endogenous DNA damage. Following ionizing radiation (IR), the mutant mice displayed higher levels of DNA breaks and stronger induction of p53 and p21, but continued DNA synthesis, reduced apoptosis, and accelerated tumor development. The differences in p21 induction, DNA synthesis and apoptosis between wild-type and mutant mice were substantially more pronounced in the mammary gland than in the intestine, suggesting a potential contributing factor to the increased risk and the tissue specificity of BRCA/PALB2-associated tumor development. Moreover, the mutant mice showed higher levels of reactive oxygen species (ROS) and constitutive activation of NFκB, an anti-apoptotic transcription factor inducible by both DNA damage and oxidative stress. Treatment of the mutant mice with an inhibitor of NFκB reactivated apoptosis and delayed tumor development following radiation. Thus, our results also suggest a pro-survival and pro-oncogenic role of NFκB in PALB2 mutant cells.

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