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Gene Review

GCN3  -  translation initiation factor eIF2B...

Saccharomyces cerevisiae S288c

Synonyms: AAS2, GCD complex subunit GCN3, Guanine nucleotide exchange factor subunit GCN3, TIF221, Transcriptional activator GCN3, ...
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Disease relevance of GCN3

  • Overexpressing only GCD2 and GCD7 also reduced eIF2(alphaP) toxicity, presumably by titrating GCN3 from eIF2B and producing the four-subunit form of eIF2B that is less sensitive to eIF2(alphaP) [1].

High impact information on GCN3

  • Using an affinity-binding assay, we show that an eIF2B subcomplex of the GCN3, GCD7, and GCD2 subunits binds to eIF2 and has a higher affinity for eIF2(alphaP), but it lacks nucleotide-exchange activity [2].
  • In addition, expression of the rat cDNA in yeast functionally complements a gcn3 deletion for the inability to induce histidine biosynthetic genes under the control of GCN4 [3].
  • The predicted amino acid sequence exhibits 42% identity to that deduced for the Saccharomyces cerevisiae GCN3 protein, the smallest subunit of yeast eIF-2B [3].
  • These mutations may identify a region in eIF-2 alpha that participates directly in a physical interaction with the GCN3 subunit of eIF-2B [4].
  • These results provide further in vivo evidence that phosphorylation of eIF-2 alpha inhibits translation by impairing eIF-2B function and identify GCN3 as a regulatory subunit of eIF-2B [5].

Biological context of GCN3

  • The amino acid sequence changes for three gcd2 mutations have been determined, and we describe several examples of mutual suppression involving the gcd2 mutations and particular alleles of GCN3 [6].
  • A deletion of four small open reading frames in the 5' leader of GCN4-lacZ mRNA mimicked the effect of a gcd1 mutation and derepressed translation of the fusion transcript in the absence of either starvation conditions or the GCN2 and GCN3 products [7].
  • We demonstrate that GCD12 and GCD2 are the same genes; however, unlike gcd12 mutations, the growth defect and constitutive derepression phenotypes associated with the gcd2-1 mutation are expressed in the presence of the wild-type GCN3 gene [8].
  • We also report the sequence of a 16 kb region from C. glabrata that contains a five-gene cluster similar to S. cerevisiae chromosome XI (including GCN3) followed by a four-gene cluster similar to chromosome XV (including HIS3) [9].
  • We describe a point mutation that adds three amino acids to the carboxyl terminus of GCN3, which inactivates its positive regulatory function required under starvation conditions without impairing its ability to promote functions carried out by GCD12 under nonstarvation conditions [10].

Associations of GCN3 with chemical compounds


Physical interactions of GCN3

  • Interestingly, a portion of the eIF-2 present in cell extracts also cofractionated and coimmunoprecipitated with these regulatory proteins but was dissociated from the GCD1/GCD2/GCN3 complex by 0.5 M KCl [12].
  • GCN3 mRNA contains no leader AUG codons, and no potential GCN4 binding sites were found in GCN3 5' noncoding DNA [10].

Regulatory relationships of GCN3

  • The GCN3 allele completely suppresses both derepression of GCN4 expression and the temperature-sensitive growth conferred by gcd 12 mutations and partially suppresses these phenotypes in gcd1 mutants [13].
  • The gcn3-102 allele is completely defective for positive regulation of GCN4 expression; however, it mimics GCN3 in suppressing gcd1 and gcd12 mutations and thus retains the ability to restore GCD function in nonstarvation conditions [13].
  • This observation suggests that GCN3 can promote or at least partially substitute for GCD2 function in normal growth conditions, while acting as an antagonist of GCD2 in amino acid starvation conditions [14].

Other interactions of GCN3

  • These allele-specific interactions have led us to propose that GCN3 and GCD2 directly interact in the GCD-eIF-2B complex [6].
  • In addition, the gcd1-101 mutation suppressed the low translational efficiency of GCN4-lacZ mRNA observed in gcn2- and gcn3- cells [7].
  • All of the mutations lead to constitutive derepression of HIS4 transcription in the absence of the GCN2+ and GCN3+ alleles [15].
  • Mutation of other components of this regulatory circuit such as GCN1 and GCN3 also resulted in improved NaCl tolerance [16].
  • Genomic differences between Candida glabrata and Saccharomyces cerevisiae around the MRPL28 and GCN3 loci [9].


  1. Identification of a regulatory subcomplex in the guanine nucleotide exchange factor eIF2B that mediates inhibition by phosphorylated eIF2. Yang, W., Hinnebusch, A.G. Mol. Cell. Biol. (1996) [Pubmed]
  2. eIF2 independently binds two distinct eIF2B subcomplexes that catalyze and regulate guanine-nucleotide exchange. Pavitt, G.D., Ramaiah, K.V., Kimball, S.R., Hinnebusch, A.G. Genes Dev. (1998) [Pubmed]
  3. Molecular cloning and characterization of cDNA encoding the alpha subunit of the rat protein synthesis initiation factor eIF-2B. Flowers, K.M., Kimball, S.R., Feldhoff, R.C., Hinnebusch, A.G., Jefferson, L.S. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  4. Mutations in the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2 alpha) that overcome the inhibitory effect of eIF-2 alpha phosphorylation on translation initiation. Vazquez de Aldana, C.R., Dever, T.E., Hinnebusch, A.G. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  5. Mammalian eukaryotic initiation factor 2 alpha kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast. Dever, T.E., Chen, J.J., Barber, G.N., Cigan, A.M., Feng, L., Donahue, T.F., London, I.M., Katze, M.G., Hinnebusch, A.G. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  6. Guanine nucleotide exchange factor for eukaryotic translation initiation factor 2 in Saccharomyces cerevisiae: interactions between the essential subunits GCD2, GCD6, and GCD7 and the regulatory subunit GCN3. Bushman, J.L., Foiani, M., Cigan, A.M., Paddon, C.J., Hinnebusch, A.G. Mol. Cell. Biol. (1993) [Pubmed]
  7. A hierarchy of trans-acting factors modulates translation of an activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. Hinnebusch, A.G. Mol. Cell. Biol. (1985) [Pubmed]
  8. gcd12 mutations are gcn3-dependent alleles of GCD2, a negative regulator of GCN4 in the general amino acid control of Saccharomyces cerevisiae. Paddon, C.J., Hinnebusch, A.G. Genetics (1989) [Pubmed]
  9. Genomic differences between Candida glabrata and Saccharomyces cerevisiae around the MRPL28 and GCN3 loci. Walsh, D.W., Wolfe, K.H., Butler, G. Yeast (2002) [Pubmed]
  10. Molecular analysis of GCN3, a translational activator of GCN4: evidence for posttranslational control of GCN3 regulatory function. Hannig, E.M., Hinnebusch, A.G. Mol. Cell. Biol. (1988) [Pubmed]
  11. Inhibition of translation initiation by volatile anesthetics involves nutrient-sensitive GCN-independent and -dependent processes in yeast. Palmer, L.K., Shoemaker, J.L., Baptiste, B.A., Wolfe, D., Keil, R.L. Mol. Biol. Cell (2005) [Pubmed]
  12. Complex formation by positive and negative translational regulators of GCN4. Cigan, A.M., Foiani, M., Hannig, E.M., Hinnebusch, A.G. Mol. Cell. Biol. (1991) [Pubmed]
  13. Interactions between positive and negative regulators of GCN4 controlling gene expression and entry into the yeast cell cycle. Harashima, S., Hannig, E.M., Hinnebusch, A.G. Genetics (1987) [Pubmed]
  14. Amino acid sequence similarity between GCN3 and GCD2, positive and negative translational regulators of GCN4: evidence for antagonism by competition. Paddon, C.J., Hannig, E.M., Hinnebusch, A.G. Genetics (1989) [Pubmed]
  15. Multiple GCD genes required for repression of GCN4, a transcriptional activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. Harashima, S., Hinnebusch, A.G. Mol. Cell. Biol. (1986) [Pubmed]
  16. The protein kinase Gcn2p mediates sodium toxicity in yeast. Goossens, A., Dever, T.E., Pascual-Ahuir, A., Serrano, R. J. Biol. Chem. (2001) [Pubmed]
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