title: Detoxification: a novel function of BRCA1 in tumor suppression?
abstract: Our studies found that BRCA1 levels negatively correlate with DNA adducts induced by Benzo(a)pyrene (BaP). Pulse-chase experiments showed that the increase in BaP-induced DNA adducts in BRCA1 knockdown cells may not be associated with BRCA1's function in nucleotide excision repair activity; rather, it may be associated with its function in modulating transcriptional regulation. BRCA1 knockdown in MCF-10A cells significantly attenuated the induction of CYP1A1 following BaP treatment indicating that the increase in BaP-induced adducts in BRCA1 knockdown cells is not CYP1A1 dependent. However, our study shows that BRCA1 defective cells may still be able to biotransform BaP by regulating other CYP enzymes, including CYP1B1. Knockdown of BRCA1 also severely affected the expression levels of two types of uridine diphosphate glucorunyltransferase (UGT1A1 and UGT1A9) and NRF2. Both UGTs are known as BaP-specific detoxification enzymes, and NRF2 is a master regulator of antioxidant and detoxification genes. Thus, we concluded that the increased amount of BaP-induced DNA adducts in BRCA1 knockdown cells is strongly associated with its loss of functional detoxification. Chromatin immunoprecipitation assay revealed that BRCA1 is recruited to the promoter/enhancer sequences of UGT1A1, UGT1A9, and NRF2. Regulation of UGT1A1 and UGT1A9 expression showed that the induction of DNA adducts by BaP is directly affected by their expression levels. Finally, overexpression of UGTs, NRF2, or ARNT significantly decreased the amount of BaP-induced adducts in BRCA1-deficient cells. Overall, our results suggest that BRCA1 protects cells by reducing the amount of BaP-induced DNA adducts possibly via transcriptional activation of detoxification gene expression.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Hong
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Olga C
authors.initials: OC
authors.lastname: Rodriguez
authors.forename: Raghu G
authors.initials: RG
authors.lastname: Nath
authors.forename: Elena M
authors.initials: EM
authors.lastname: Tilli
authors.forename: Christopher
authors.initials: C
authors.lastname: Albanese
authors.forename: Fung-Lung
authors.initials: FL
authors.lastname: Chung
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Kwon
authors.forename: Insoo
authors.initials: I
authors.lastname: Bae
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001711:Biotransformation; D015153:Blotting, Western; D002274:Carcinogens, Environmental / Q000633:toxicity; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts / Q000032:analysis*; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D015262:Xenobiotics / Q000633:toxicity
chemical_list: D019313:BRCA1 Protein; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D034741:RNA, Small Interfering; D015262:Xenobiotics; D001564:Benzo(a)pyrene; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D014453:Glucuronosyltransferase