BRCA1 transcriptional activity is enhanced by interactions between its AD1 domain and AhR

Abstract

Purpose : We previously reported that BRCA1 interacts with aryl hydrocarbon receptor nuclear translocator (ARNT) and that this interaction affects TCDD-induced CYP1A1 gene expression (Kang et al., J Biol Chem 281:14654–14662, 2006). In this study we continue this investigation and begin to define the significance of this interaction for the regulation of stress-induced transcription. Methods : Immunoprecipitations (IPs), western blot (WB) analysis, GST pull-down assays and promoter reporter assays were used to investigate whether the aryl hydrocarbon receptor (AhR) can regulate transcription that is dependent on the activation domain 1 (AD1) domain of BRCA1. Results : We show that AhR, a transcription factor, can bind specifically to AD1 in the C-terminal region of BRCA1 and affect BRCA1’s ability to regulate transcription activity. We found that xenobiotics that positively and negatively affect AhR’s activity as a transcription factor (e.g., dioxin and α-naphthoflavone, respectively), have similar effects on AhR’s ability to affect AD1-domain-dependent transcription. These physical and functional AhR–AD1 interactions may require the coiled-coil motif in AD1 because point-mutations in this motif reduce these interactions. Conclusion : Xenobiotic-activated AhR can function in two ways, as a component of the AhR/ARNT transcription factor and a regulator of AD1-dependent transcription. Consequently, BRCA1 has two distinct mechanisms for sensing xenobiotics and regulating AhR-dependent stress responses to these xenobiotics. We speculate that the normal functioning of this interaction could play a role in BRCA1’s tumor suppressing ability. Keywords : BRCA1 – AD1 – AhR – JunB – Xenobiotic stress – Transcription regulation