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Gene Review

HAP1  -  Hap1p

Saccharomyces cerevisiae S288c

Synonyms: CYP1, CYP1 activatory protein, Heme activator protein 1, Heme-responsive zinc finger transcription factor HAP1, L9672.1, ...
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High impact information on HAP1

  • While sequences between 445 and 1308 have no obvious function, a highly acidic carboxyl terminus mediates transcriptional activation by HAP1 [1].
  • We present the DNA sequence and a functional dissection of the 1483 residue yeast activator HAP1 [1].
  • The CYC1 and CYC7 sites compete for binding to HAP1 and have comparable affinities for the protein [2].
  • Yeast HAP1 activator competes with the factor RC2 for binding to the upstream activation site UAS1 of the CYC1 gene [3].
  • Several yeast upstream transcriptional activators, such as GCN4, GAL4 and HAP1, seem to contain separate domains for binding to DNA and activating transcription [4].

Biological context of HAP1

  • The binding site was compared to the HAP1-binding sequences previously characterized in detail (UAS1CYC1, UASCYC7) [5].
  • The HAP1-binding sequence was localized by using DNA fragments spanning different regions, by DNase I footprinting and by methylation interference of DNA-protein binding [5].
  • This asymmetry aligns the Zn2Cys6 domains in a tandem head-to-tail fashion to contact two DNA half sites, positions an N-terminal arm of one of the protein subunits to interact with the inter-half site base pairs in the DNA minor groove, and suggests a mechanism by which DNA-binding facilitates asymmetric dimerization by HAP1 [6].
  • These findings are discussed in the context of two models that suggest how the DNA sequence can alter the activity of the bound HAP1 [7].
  • This finding shows that a zinc finger anchors DNA binding to both types of HAP1 sites [7].

Anatomical context of HAP1

  • Interestingly, heme also potentiates binding of the yeast transcriptional activator HAP1 to DNA and inhibits mitochondrial import of the mammalian delta-aminolevulinate synthase (ALAS) and the catalytic activity of the reticulocyte kinase, HRI [8].
  • Resistance to peroxide was also inducible in an isogenic petite and an isogenic strain with a mutation in the HAP1 gene, indicating that the adaptive response does not require functional mitochondria [9].

Associations of HAP1 with chemical compounds

  • The hap1 mutant grew at near-normal rates on glycerol, whereas hap2 and hap3 mutants grew very slowly [10].
  • The mutation associated with this novel allele of HAP1 was localized to a glycine to aspartate change in amino acid 235 of HAP1, between the DNA binding and heme responsive domains [11].
  • Activation is achieved through one of two transcriptional activators, the heme-dependent HAP1 protein or the heme-activated, glucose-repressed HAP2/3/4 complex [12].
  • The C6 zinc cluster dictates asymmetric binding by HAP1 [13].
  • PUT1 is inducible by proline, responds only slightly to carbon catabolite repression, and is not regulated by the cytochrome activator proteins HAP1 and HAP2 [14].

Physical interactions of HAP1

  • As demonstrated by a gel retardation assay, the HAP1 protein binds to a heme control region of the CTT1 gene [5].
  • We have determined the 2.5 A crystal structure of HAP1 bound to a cognate upstream activation sequence from the CYC7 gene [6].
  • Within this region the binding sites for both the Hap2/3/4/5 complex and Hap1p were defined by gel retardation experiments and site-directed mutagenesis [15].
  • First, while CYC1 contains two sites that bind HAP1 cooperatively, CYT1 has a single high-affinity site [16].
  • The yeast transcriptional activator HAP1 contains a DNA-binding domain homologous to GAL4, PPR1, and related factors [17].

Regulatory relationships of HAP1

  • The results show that in anaerobic and in heme-deficient cells, CYP1 activates the transcription of HEM13 and inhibits that of 14DM [18].
  • It appears likely that HRM7 and Hsp90 act together to promote the Hap1 conformational changes that are necessary for Hap1 activation [19].
  • The Hsp70-Ydj1 molecular chaperone represses the activity of the heme activator protein Hap1 in the absence of heme [20].
  • In this study, we show that Hap1p is the main transcriptional activator involved in the control of CYB2 transcription [21].
  • Finally, mTPx I also induced by t-butyl hydroperoxide in a Hap1p-independent manner [22].

Other interactions of HAP1

  • The mutant with the largest deletion, mini-HAP1, has no measurable activity at CYC7 but binds normally to the site in vitro [7].
  • The effect of heme on HMG1 expression was mediated by the HAP1 transcriptional regulator and was independent of HAP2 [23].
  • ARE2 requires the HAP1 transcription factor for optimal expression, and both ARE genes are derepressed in a rox1 (repressor of oxygen) mutant genetic background [24].
  • We therefore examined the role of the heme-dependent transcriptional activator Hap1p and the carbon source-dependent Hap2/3/4/5 complex [15].
  • The repression of hypoxic genes under normoxic conditions results from Hap1-mediated activation of ROX1 transcription [25].

Analytical, diagnostic and therapeutic context of HAP1

  • Two congenic upc2-1 strains, differing quantitatively in aerobic sterol uptake due to a modifying mutation in the HAP1 transcription factor, were compared using DNA microarrays [26].
  • Functional dissection and sequence of yeast HAP1 activator [1].
  • Titration of the high molecular weight complex by addition of a non-DNA-binding form of HAP1 allows the protein to form dimeric complexes in the absence of heme in vitro and acquires partial transcriptional activity in vivo [27].


  1. Functional dissection and sequence of yeast HAP1 activator. Pfeifer, K., Kim, K.S., Kogan, S., Guarente, L. Cell (1989) [Pubmed]
  2. Yeast HAP1 activator binds to two upstream activation sites of different sequence. Pfeifer, K., Prezant, T., Guarente, L. Cell (1987) [Pubmed]
  3. Yeast HAP1 activator competes with the factor RC2 for binding to the upstream activation site UAS1 of the CYC1 gene. Pfeifer, K., Arcangioli, B., Guarente, L. Cell (1987) [Pubmed]
  4. Mutations that alter transcriptional activation but not DNA binding in the zinc finger of yeast activator HAPI. Kim, K.S., Guarente, L. Nature (1989) [Pubmed]
  5. Co-ordinate control of synthesis of mitochondrial and non-mitochondrial hemoproteins: a binding site for the HAP1 (CYP1) protein in the UAS region of the yeast catalase T gene (CTT1). Winkler, H., Adam, G., Mattes, E., Schanz, M., Hartig, A., Ruis, H. EMBO J. (1988) [Pubmed]
  6. Structure of a HAP1-DNA complex reveals dramatically asymmetric DNA binding by a homodimeric protein. King, D.A., Zhang, L., Guarente, L., Marmorstein, R. Nat. Struct. Biol. (1999) [Pubmed]
  7. Internal deletions in the yeast transcriptional activator HAP1 have opposite effects at two sequence elements. Kim, K.S., Pfeifer, K., Powell, L., Guarente, L. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  8. Heme binds to a short sequence that serves a regulatory function in diverse proteins. Zhang, L., Guarente, L. EMBO J. (1995) [Pubmed]
  9. Inducibility of the response of yeast cells to peroxide stress. Collinson, L.P., Dawes, I.W. J. Gen. Microbiol. (1992) [Pubmed]
  10. Effects of hap mutations on heme and cytochrome formation in yeast. Mattoon, J.R., Caravajal, E., Guthrie, D. Curr. Genet. (1990) [Pubmed]
  11. A novel allele of HAP1 causes uninducible expression of HEM13 in Saccharomyces cerevisiae. Ushinsky, S.C., Keng, T. Genetics (1994) [Pubmed]
  12. Regulation of gene expression by oxygen in Saccharomyces cerevisiae. Zitomer, R.S., Lowry, C.V. Microbiol. Rev. (1992) [Pubmed]
  13. The C6 zinc cluster dictates asymmetric binding by HAP1. Zhang, L., Guarente, L. EMBO J. (1996) [Pubmed]
  14. Proline utilization in Saccharomyces cerevisiae: sequence, regulation, and mitochondrial localization of the PUT1 gene product. Wang, S.S., Brandriss, M.C. Mol. Cell. Biol. (1987) [Pubmed]
  15. Regulation of the Saccharomyces cerevisiae DLD1 gene encoding the mitochondrial protein D-lactate ferricytochrome c oxidoreductase by HAP1 and HAP2/3/4/5. Lodi, T., Alberti, A., Guiard, B., Ferrero, I. Mol. Gen. Genet. (1999) [Pubmed]
  16. Regulation of the yeast CYT1 gene encoding cytochrome c1 by HAP1 and HAP2/3/4. Schneider, J.C., Guarente, L. Mol. Cell. Biol. (1991) [Pubmed]
  17. The yeast activator HAP1--a GAL4 family member--binds DNA in a directly repeated orientation. Zhang, L., Guarente, L. Genes Dev. (1994) [Pubmed]
  18. CYP1 (HAP1) is a determinant effector of alternative expression of heme-dependent transcribed genes in yeast [corrected]. Verdière, J., Gaisne, M., Labbe-Bois, R. Mol. Gen. Genet. (1991) [Pubmed]
  19. Structural environment dictates the biological significance of heme-responsive motifs and the role of Hsp90 in the activation of the heme activator protein Hap1. Lee, H.C., Hon, T., Lan, C., Zhang, L. Mol. Cell. Biol. (2003) [Pubmed]
  20. The Hsp70-Ydj1 molecular chaperone represses the activity of the heme activator protein Hap1 in the absence of heme. Hon, T., Lee, H.C., Hach, A., Johnson, J.L., Craig, E.A., Erdjument-Bromage, H., Tempst, P., Zhang, L. Mol. Cell. Biol. (2001) [Pubmed]
  21. Regulation of the CYB2 gene expression: transcriptional co-ordination by the Hap1p, Hap2/3/4/5p and Adr1p transcription factors. Ramil, E., Agrimonti, C., Shechter, E., Gervais, M., Guiard, B. Mol. Microbiol. (2000) [Pubmed]
  22. Regulation of mitochondrial thioredoxin peroxidase I expression by two different pathways: one dependent on cAMP and the other on heme. Monteiro, G., Pereira, G.A., Netto, L.E. Free Radic. Biol. Med. (2002) [Pubmed]
  23. Positive and negative transcriptional control by heme of genes encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase in Saccharomyces cerevisiae. Thorsness, M., Schafer, W., D'Ari, L., Rine, J. Mol. Cell. Biol. (1989) [Pubmed]
  24. Transcriptional regulation of the two sterol esterification genes in the yeast Saccharomyces cerevisiae. Jensen-Pergakes, K., Guo, Z., Giattina, M., Sturley, S.L., Bard, M. J. Bacteriol. (2001) [Pubmed]
  25. A microarray-assisted screen for potential Hap1 and Rox1 target genes in Saccharomyces cerevisiae. Ter Linde, J.J., Steensma, H.Y. Yeast (2002) [Pubmed]
  26. Transcriptional profiling identifies two members of the ATP-binding cassette transporter superfamily required for sterol uptake in yeast. Wilcox, L.J., Balderes, D.A., Wharton, B., Tinkelenberg, A.H., Rao, G., Sturley, S.L. J. Biol. Chem. (2002) [Pubmed]
  27. HAP1 is nuclear but is bound to a cellular factor in the absence of heme. Zhang, L., Guarente, L. J. Biol. Chem. (1994) [Pubmed]
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