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Gene Review

CUP2  -  Cup2p

Saccharomyces cerevisiae S288c

Synonyms: ACE1, Copper-fist transcription factor, G1810, Transcriptional activator protein CUP2, YGL166W
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Disease relevance of CUP2

  • Using mobility shift, methylation interference, and DNase I and hydroxyl radical footprinting assays, we examined the interaction of wild-type and variant CUP2 proteins produced in Escherichia coli with the UASc [1].
  • However, the toxicity of cisplatin in cells with a disrupted gene for ACE1, a factor that regulates transcription of the yeast gene for metallothionein, was also significantly reduced by treatment with copper [2].

High impact information on CUP2

  • However, TAF17-depleted cells maintain Ace1-dependent activation, and they induce de novo activation by heat shock factor in a manner predominantly associated with the activator, not the core promoter [3].
  • Here we report the identification of a nuclear protein from S. cerevisiae, MAC1, whose N-terminal region is highly similar to the copper and DNA binding domains of ACE1 and AMT1 [4].
  • ACE1 and AMT1 are 'copper-fist' transcription factors which possess a conserved cysteine-rich copper binding domain required for DNA binding [4].
  • The CUP2 gene product regulates the expression of the CUP1 gene, coding for yeast metallothionein [5].
  • The functional importance of this DNA-protein interaction is demonstrated by the facts that (i) copper induction of SOD1 mRNA does not occur in a strain lacking ACE1 and (ii) it does not occur in a strain containing a genetically engineered SOD1 promoter that lacks a functional ACE1 binding site [6].

Biological context of CUP2

  • We show that CUP2, which is on chromosome VII, codes for or controls the synthesis or activity of a protein which binds the upstream control region of the CUP1 gene on chromosome VIII [5].
  • CUP2 mutant alleles from Cu-sensitive yeast strains have point mutations affecting the DNA-binding activity [7].
  • We have isolated a gene, designated ACE2, which when present on a high-copy-number plasmid suppresses the copper-sensitive phenotype of an ace1-deletion strain [8].
  • Induction requires the ACE1 gene product, which binds to specific sites in the promoter region of the CUP1 gene [8].
  • In this study, we found that deleting the entire coding sequence of the ACE1 gene resulted in a decrease in basal-level transcription of CUP1 to low but detectable levels and conferred a copper-sensitive phenotype to the cells [8].

Anatomical context of CUP2

  • The ability of a bifunctional ACE1-beta-galactosidase fusion protein to accumulate in yeast cell nuclei was consistent with the possibility that ACE1 plays a direct role in the regulation of copper-inducible transcription of the yeast metallothionein gene [9].

Associations of CUP2 with chemical compounds

  • The CUP2 protein contains a cysteine-rich DNA-binding domain dependent on Cu+ and Ag+ ions which bind the cysteine residues and direct the refolding of the metal-free apoprotein [7].
  • Using an ethyl methanesulfonate mutant of a yeast strain in which CUP1 and ACE1 were deleted, we isolated a gene, designated CUP9, which permits yeast cells to grow at high concentrations of environmental copper, most notably when lactate is the sole carbon source [10].
  • In vivo dimethyl sulfate footprinting analysis of the CUP1 promoter demonstrated transient occupation of the metal response elements by Ace1p which paralleled CUP1 mRNA expression [11].
  • The results are consistent with the N-terminal halves of AMT1 and ACE1 consisting of two independent submodules, one binding a single Zn(II) ion and the second binding the tetracopper cluster [12].
  • Moreover, this inhibition appears to be a result of a direct interaction between Ace1 thiols and HNO and not a result of any chemistry associated with HNO-derived species [13].

Physical interactions of CUP2


Regulatory relationships of CUP2

  • These studies (i) demonstrate that the nutritional and toxic copper metalloregulatory transcription factors Mac1p and Ace1p must sense and respond to copper ions in a dynamic fashion to appropriately regulate copper ion homeostasis and (ii) establish the requirement for a wild-type Mac1p for survival in the presence of toxic copper levels [11].
  • By contrast, transcription of CUP1 mediated by both Hsf1 and copper-activated transcription factor Ace1 was inducible after inactivating TFIIE [14].

Other interactions of CUP2

  • Strains with a complete deletion of the ACE1 gene, the copper-dependent activator of CUP1 transcription, are hypersensitive to copper [15].

Analytical, diagnostic and therapeutic context of CUP2

  • Considering the similarity of metal-thiolate ligation in Ace1 with other mammalian metalloproteins such as metallothionein, metal chaperones, and zinc-finger proteins, these results help to understand the biochemical interactions of NO with those mammalian metalloproteins [16].
  • Similarly, in vivo cross-linking and chromatin immunoprecipitation assays demonstrate association of DmORC with both ACE3 and two other amplification control elements, AER-d and ACE1 [17].


  1. A single amino acid change in CUP2 alters its mode of DNA binding. Buchman, C., Skroch, P., Dixon, W., Tullius, T.D., Karin, M. Mol. Cell. Biol. (1990) [Pubmed]
  2. Copper(II) protects yeast against the toxicity of cisplatin independently of the induction of metallothionein and the inhibition of platinum uptake. Ohashi, K., Kajiya, K., Inaba, S., Hasegawa, T., Seko, Y., Furuchi, T., Naganuma, A. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  3. The histone H3-like TAF is broadly required for transcription in yeast. Moqtaderi, Z., Keaveney, M., Struhl, K. Mol. Cell (1998) [Pubmed]
  4. MAC1, a nuclear regulatory protein related to Cu-dependent transcription factors is involved in Cu/Fe utilization and stress resistance in yeast. Jungmann, J., Reins, H.A., Lee, J., Romeo, A., Hassett, R., Kosman, D., Jentsch, S. EMBO J. (1993) [Pubmed]
  5. The CUP2 gene product regulates the expression of the CUP1 gene, coding for yeast metallothionein. Welch, J., Fogel, S., Buchman, C., Karin, M. EMBO J. (1989) [Pubmed]
  6. ACE1, a copper-dependent transcription factor, activates expression of the yeast copper, zinc superoxide dismutase gene. Gralla, E.B., Thiele, D.J., Silar, P., Valentine, J.S. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  7. The CUP2 gene product, regulator of yeast metallothionein expression, is a copper-activated DNA-binding protein. Buchman, C., Skroch, P., Welch, J., Fogel, S., Karin, M. Mol. Cell. Biol. (1989) [Pubmed]
  8. ACE2, an activator of yeast metallothionein expression which is homologous to SWI5. Butler, G., Thiele, D.J. Mol. Cell. Biol. (1991) [Pubmed]
  9. A cysteine-rich nuclear protein activates yeast metallothionein gene transcription. Szczypka, M.S., Thiele, D.J. Mol. Cell. Biol. (1989) [Pubmed]
  10. Identification and analysis of a Saccharomyces cerevisiae copper homeostasis gene encoding a homeodomain protein. Knight, S.A., Tamai, K.T., Kosman, D.J., Thiele, D.J. Mol. Cell. Biol. (1994) [Pubmed]
  11. Dynamic regulation of copper uptake and detoxification genes in Saccharomyces cerevisiae. Peña, M.M., Koch, K.A., Thiele, D.J. Mol. Cell. Biol. (1998) [Pubmed]
  12. Identification of the Zn(II) site in the copper-responsive yeast transcription factor, AMT1: a conserved Zn module. Farrell, R.A., Thorvaldsen, J.L., Winge, D.R. Biochemistry (1996) [Pubmed]
  13. Nitroxyl-mediated disruption of thiol proteins: inhibition of the yeast transcription factor Ace1. Cook, N.M., Shinyashiki, M., Jackson, M.I., Leal, F.A., Fukuto, J.M. Arch. Biochem. Biophys. (2003) [Pubmed]
  14. Activator-specific requirement for the general transcription factor IIE in yeast. Sakurai, H., Fukasawa, T. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  15. Heat shock transcription factor activates transcription of the yeast metallothionein gene. Silar, P., Butler, G., Thiele, D.J. Mol. Cell. Biol. (1991) [Pubmed]
  16. Mechanisms of nitrogen oxide-mediated disruption of metalloprotein function: an examination of the copper-responsive yeast transcription factor Ace1. Shinyashiki, M., Pan, C.J., Switzer, C.H., Fukuto, J.M. Chem. Res. Toxicol. (2001) [Pubmed]
  17. Drosophila ORC specifically binds to ACE3, an origin of DNA replication control element. Austin, R.J., Orr-Weaver, T.L., Bell, S.P. Genes Dev. (1999) [Pubmed]
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