ATOX1: a novel copper-responsive transcription factor in mammals?

As the trace element copper is essential, but extremely toxic in high concentrations, intracellular copper concentrations are tightly controlled. Once in the cell, copper is distributed by metallochaperones, including the small cytoplasmic protein ATOX1. ATOX1 plays an important role in the transfer of copper to the copper export P-type ATPases ATP7A and ATP7B to facilitate copper excretion. Recently, a novel function for Atox1 as a transcription factor (TF) regulating Ccnd1 was proposed. Crystal structures of ATOX1 reveal copper-dependent homodimerization of ATOX1. As many TFs regulate gene expression as a dimer and bind to DNA repeats, we investigated the promotor region of CCND1 and detected a direct repeat sequence in the Atox1 binding site (tentatively referred to as CABE, copper-responsive Atox1 binding element). We therefore propose copper-dependent homodimerization to be an essential step in the regulation of ATOX1-dependent transcription.