MAC1, A NUCLEAR REGULATORY PROTEIN RELATED TO CU-DEPENDENT TRANSCRIPTION FACTORS IS INVOLVED IN CU FE UTILIZATION AND STRESS RESISTANCE IN YEAST/

The related transcription factors ACE1 of Saccharomyces cerevisiae and AMT1 of Candida glabrata are involved in copper metabolism by activat ing the transcription of copper metallothionein genes. ACE1 and AMT1 a re 'copper-rist' transcription factors which possess a conserved cyste ine-rich copper binding domain required for DNA binding. Here we repor t the identification of a nuclear protein from S.cerevisiae, MAC1, who se N-terminal region is highly similar to the copper and DNA binding d omains of ACE1 and AMT1. Loss-of-function mutants of MAC1 have a defec t in the plasma membrane Cu(II) and Fe(III) reductase activity, are sl ow growing, respiratory deficient, and hypersensitive to heat and expo sure to cadmium, zinc, lead and H2O2. Conversely, a dominant gain-of-f unction mutant of MAC1 shows an elevated reductase activity and is hyp ersensitive to copper. We have identified two target genes of MAC1 who se altered expression in mutants of MAC1 can account for some of the o bserved mutant phenotypes. First, MAC1 is involved in basal level tran scription of FRE1, encoding a plasma membrane component associated wit h both Cu(II) and Fe(III) reduction. Second, MAC1 is involved in the H 2O2-induced transcription of CTT1, encoding the cytosolic catalase. Th is suggests that MAC1 may encode a novel metal-fist transcription fact or required for both basal and regulated transcription of genes involv ed in Cu/Fe utilization and the stress response.