PALB2/FANCN is mutated or silenced in breast, ovarian and pancreatic cancers and Fanconi anemia. It was initially discovered as a major binding protein for BRCA2 and controls the function of BRCA2 in homologous recombination, DNA double strand break repair and tumor suppression (Xia et al 2006). Nowadays, PALB2 itself has been also identified as a BRCA2-like breast cancer susceptibility protein and links BRCA1 and BRCA2 in the DNA damage response (Zhang and Ma et al 2009, Sy et al 2009). Therefore, PALB2 has been thought as an integral component of BRCA complex required for maintaining genomic stability via DNA recombinational repair.
In order to explore what other functions PALB2 protein may have, we performed a comprehensive search of PALB2-binding partners using the tandem affinity purification (TAP) assay combined with tandem mass spectrometry (LC-MS/MS) analysis. We show that PALB2 directly interacts with KEAP1, an oxidative stress sensor that binds and represses the anti-oxidant transcription factor NRF2. NRF2-KEAP1 pathway has been characterized as an important endogenous mechanism for combating oxidative stress. Oxidative stress-induced damage can lead to a variety of pathologies such as cancer, Parkinson's diseases, diabetes, Alzheimer's diseases and the aging process (Valko et al 2007). We demonstrate that PALB2 shares a conserved “ETGE” motif with NRF2 and competes with NRF2 for KEAP1 binding, thereby relieving NRF2 from KEAP1-mediated repression. As such, PALB2 promotes NRF2 nuclear accumulation, protects cells against oxidative stress and reduces cellular level of reactive oxygen species (ROS). Our findings establish a new function for PALB2 and provide a direct link between oxidative stress and the predisposition of cancer and Fanconi anemia.
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Citation Information: Clin Cancer Res 2010;16(14 Suppl):B40.