Detoxification: A Novel Function of BRCA1 in Tumor Suppression?

• DOI: 10.1093/toxsci/kfr089
• Publication Date: 2011-04-21T00:39:42Z
• Authors: Hyo Jin Kang; Young Bin Hong; Hee Jeong Kim; Olga C. Rodriguez; Raghu G. Nath; Elena M. Tilli; Christopher Albanese; Fung-Lung Chung; Sang Hoon Kwon; Insoo Bae
• Keywords: Chromatin immunoprecipitation

Our studies found that BRCA1 levels negatively correlate with DNA adducts induced by Benzo(a)pyrene (BaP). Pulse-chase experiments showed the increase in BaP-induced knockdown cells may not be associated BRCA1's function nucleotide excision repair activity; rather, it its modulating transcriptional regulation. MCF-10A significantly attenuated induction of CYP1A1 following BaP treatment indicating is dependent. However, our study shows defective still able to biotransform regulating other CYP enzymes, including CYP1B1. Knockdown also severely affected expression two types uridine diphosphate glucorunyltransferase (UGT1A1 and UGT1A9) NRF2. Both UGTs are known as BaP-specific detoxification NRF2 a master regulator antioxidant genes. Thus, we concluded increased amount strongly loss functional detoxification. Chromatin immunoprecipitation assay revealed recruited promoter/enhancer sequences UGT1A1, UGT1A9, Regulation UGT1A1 UGT1A9 directly their levels. Finally, overexpression UGTs, NRF2, or ARNT decreased BRCA1-deficient cells. Overall, results suggest protects reducing possibly via activation gene expression.