Copper is an indispensable metal for life. For convenience of genetic 
manipulation and sharing similar metabolic pathway of metals with mammalian 
cells, the yeast Saccharomyces cerevisiae is widely used for metal homeostasis 
studies. Storage and mobilization of copper ions in yeast vacuoles or mammalian 
lysosomes are important for cells to avoid their toxicity and elevate their 
utility. Though regulation of other genes involved in copper homeostasis is well 
understood, the regulation of gene encoding low-affinity copper transporter 
Ctr2p, which mediates mobilization of vacuolar or lysosomal stored copper ions, 
is still unclear. In this study, we found that copper depletion can upregulate 
yeast CTR2 gene transcription while copper overload downregulate it. The 
copper-depletion induced CTR2 transcription can be abrogated by genetic deletion 
of copper-sensing transcription factor Mac1p. Though absent of consensus Mac1p 
binding sequences, CTR2 promoter region is demonstrated to be occupied by Mac1p, 
according to our results of chromatin immunoprecipitation (ChIP) assay. 
Overexpression of Mac1p can upregulate CTR2 transcription and partially 
complement the growth defect of copper-deficient yeast strain. Taken together, 
our results suggest that Mac1p can activate the expression of vacuolar copper 
transporter Ctr2p in response to copper deficiency, resulting in yeast 
resistance to copper starvation.