Logo of geneticsGeneticsCurrent IssueInformation for AuthorsEditorial BoardSubscribeSubmit a Manuscript
Genetics. 1998 Jul; 149(3): 1495–1509.
PMCID: PMC1460234

Isolation of the gene encoding the Drosophila melanogaster homolog of the Saccharomyces cerevisiae GCN2 eIF-2alpha kinase.


Genomic and cDNA clones homologous to the yeast GCN2 eIF-2alpha kinase (yGCN2) were isolated from Drosophila melanogaster. The identity of the Drosophila GCN2 (dGCN2) gene is supported by the unique combination of sequence encoding a protein kinase catalytic domain and a domain homologous to histidyl-tRNA synthetase and by the ability of dGCN2 to complement a deletion mutant of the yeast GCN2 gene. Complementation of Deltagcn2 in yeast by dGCN2 depends on the presence of the critical regulatory phosphorylation site (serine 51) of eIF-2alpha. dGCN2 is composed of 10 exons encoding a protein of 1589 amino acids. dGCN2 mRNA is expressed throughout Drosophila development and is particularly abundant at the earliest stages of embryogenesis. The dGCN2 gene was cytogenetically and physically mapped to the right arm of the third chromosome at 100C3 in STS Dm2514. The discovery of GCN2 in higher eukaryotes is somewhat unexpected given the marked differences between the amino acid biosynthetic pathways of yeast vs. Drosophila and other higher eukaryotes. Despite these differences, the presence of GCN2 in Drosophila suggests at least partial conservation from yeast to multicellular organisms of the mechanisms responding to amino acid deprivation.

Full Text

The Full Text of this article is available as a PDF (462K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Flaim KE, Peavy DE, Everson WV, Jefferson LS. The role of amino acids in the regulation of protein synthesis in perfused rat liver. I. Reduction in rates of synthesis resulting from amino acid deprivation and recovery during flow-through perfusion. J Biol Chem. 1982 Mar 25;257(6):2932–2938. [PubMed]
  • Gong SS, Guerrini L, Basilico C. Regulation of asparagine synthetase gene expression by amino acid starvation. Mol Cell Biol. 1991 Dec;11(12):6059–6066. [PMC free article] [PubMed]
  • Guyer D, Patton D, Ward E. Evidence for cross-pathway regulation of metabolic gene expression in plants. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4997–5000. [PMC free article] [PubMed]
  • Hanks SK, Hunter T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 1995 May;9(8):576–596. [PubMed]
  • Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988 Jul 1;241(4861):42–52. [PubMed]
  • Hinnebusch AG. Mechanisms of gene regulation in the general control of amino acid biosynthesis in Saccharomyces cerevisiae. Microbiol Rev. 1988 Jun;52(2):248–273. [PMC free article] [PubMed]
  • Anderson KV, Lengyel JA. Changing rates of DNA and RNA synthesis in Drosophila embryos. Dev Biol. 1981 Feb;82(1):127–138. [PubMed]
  • Andrulis IL, Hatfield GW, Arfin SM. Asparaginyl-tRNA aminoacylation levels and asparagine synthetase expression in cultured Chinese hamster ovary cells. J Biol Chem. 1979 Nov 10;254(21):10629–10633. [PubMed]
  • Hutson RG, Kilberg MS. Cloning of rat asparagine synthetase and specificity of the amino acid-dependent control of its mRNA content. Biochem J. 1994 Dec 15;304(Pt 3):745–750. [PMC free article] [PubMed]
  • Arnez JG, Harris DC, Mitschler A, Rees B, Francklyn CS, Moras D. Crystal structure of histidyl-tRNA synthetase from Escherichia coli complexed with histidyl-adenylate. EMBO J. 1995 Sep 1;14(17):4143–4155. [PMC free article] [PubMed]
  • Kimball SR, Jefferson LS. Mechanisms of translational control in liver and skeletal muscle. Biochimie. 1994;76(8):729–736. [PubMed]
  • Austin SA, Clemens MJ. Stimulation of protein synthesis by lysine analogues in lysine-deprived Ehrlich ascites tumour cells. Biochim Biophys Acta. 1984 May 22;804(1):16–22. [PubMed]
  • Kimball SR, Antonetti DA, Brawley RM, Jefferson LS. Mechanism of inhibition of peptide chain initiation by amino acid deprivation in perfused rat liver. Regulation involving inhibition of eukaryotic initiation factor 2 alpha phosphatase activity. J Biol Chem. 1991 Jan 25;266(3):1969–1976. [PubMed]
  • Austin SA, Pain VM, Lewis JA, Clemens MJ. Investigation of the role of uncharged tRNA in the regulation of polypeptide chain initiation by amino acid starvation in cultured mammalian cells; a reappraisal. Eur J Biochem. 1982 Mar 1;122(3):519–526. [PubMed]
  • Barber GN, Jagus R, Meurs EF, Hovanessian AG, Katze MG. Molecular mechanisms responsible for malignant transformation by regulatory and catalytic domain variants of the interferon-induced enzyme RNA-dependent protein kinase. J Biol Chem. 1995 Jul 21;270(29):17423–17428. [PubMed]
  • Blechynden LM, Lawson CM, Garlepp MJ. Sequence and polymorphism analysis of the murine gene encoding histidyl-tRNA synthetase. Gene. 1996 Oct 31;178(1-2):151–156. [PubMed]
  • Laine RO, Hutson RG, Kilberg MS. Eukaryotic gene expression: metabolite control by amino acids. Prog Nucleic Acid Res Mol Biol. 1996;53:219–248. [PubMed]
  • Cavener DR, Ray SC. Eukaryotic start and stop translation sites. Nucleic Acids Res. 1991 Jun 25;19(12):3185–3192. [PMC free article] [PubMed]
  • Lee SB, Rodríguez D, Rodríguez JR, Esteban M. The apoptosis pathway triggered by the interferon-induced protein kinase PKR requires the third basic domain, initiates upstream of Bcl-2, and involves ICE-like proteases. Virology. 1997 Apr 28;231(1):81–88. [PubMed]
  • Chen JJ, London IM. Regulation of protein synthesis by heme-regulated eIF-2 alpha kinase. Trends Biochem Sci. 1995 Mar;20(3):105–108. [PubMed]
  • Li J, Petryshyn RA. Activation of the double-stranded RNA-dependent eIF-2 alpha kinase by cellular RNA from 3T3-F442A cells. Eur J Biochem. 1991 Jan 1;195(1):41–48. [PubMed]
  • Cusack S, Härtlein M, Leberman R. Sequence, structural and evolutionary relationships between class 2 aminoacyl-tRNA synthetases. Nucleic Acids Res. 1991 Jul 11;19(13):3489–3498. [PMC free article] [PubMed]
  • Lofgren DJ, Thompson LH. Relationship between histidyl-tRNA level and protein synthesis rate in wild-type and mutant Chinese hamster ovary cells. J Cell Physiol. 1979 Jun;99(3):303–312. [PubMed]
  • Delarue M, Moras D. The aminoacyl-tRNA synthetase family: modules at work. Bioessays. 1993 Oct;15(10):675–687. [PubMed]
  • Mathews MB. Control of translation in adenovirus-infected cells. Enzyme. 1990;44(1-4):250–264. [PubMed]
  • Der SD, Yang YL, Weissmann C, Williams BR. A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3279–3283. [PMC free article] [PubMed]
  • Dever TE, Feng L, Wek RC, Cigan AM, Donahue TF, Hinnebusch AG. Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell. 1992 Feb 7;68(3):585–596. [PubMed]
  • Pain VM. Translational control during amino acid starvation. Biochimie. 1994;76(8):718–728. [PubMed]
  • Vazquez de Aldana CR, Wek RC, Segundo PS, Truesdell AG, Hinnebusch AG. Multicopy tRNA genes functionally suppress mutations in yeast eIF-2 alpha kinase GCN2: evidence for separate pathways coupling GCN4 expression to unchanged tRNA. Mol Cell Biol. 1994 Dec;14(12):7920–7932. [PMC free article] [PubMed]
  • Qu S, Perlaky SE, Organ EL, Crawford D, Cavener DR. Mutations at the Ser50 residue of translation factor eIF-2alpha dominantly affect developmental rate, body weight, and viability of Drosophila melanogaster. Gene Expr. 1997;6(6):349–360. [PubMed]
  • Wek RC. eIF-2 kinases: regulators of general and gene-specific translation initiation. Trends Biochem Sci. 1994 Nov;19(11):491–496. [PubMed]
  • Wek RC, Jackson BM, Hinnebusch AG. Juxtaposition of domains homologous to protein kinases and histidyl-tRNA synthetases in GCN2 protein suggests a mechanism for coupling GCN4 expression to amino acid availability. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4579–4583. [PMC free article] [PubMed]
  • Ramirez M, Wek RC, Vazquez de Aldana CR, Jackson BM, Freeman B, Hinnebusch AG. Mutations activating the yeast eIF-2 alpha kinase GCN2: isolation of alleles altering the domain related to histidyl-tRNA synthetases. Mol Cell Biol. 1992 Dec;12(12):5801–5815. [PMC free article] [PubMed]
  • Rannels DE, Pegg AE, Rannels SR, Jefferson LS. Effect of starvation on initiation of protein synthesis in skeletal muscle and heart. Am J Physiol. 1978 Aug;235(2):E126–E133. [PubMed]
  • Williams BR. Role of the double-stranded RNA-activated protein kinase (PKR) in cell regulation. Biochem Soc Trans. 1997 May;25(2):509–513. [PubMed]
  • Santoyo J, Alcalde J, Méndez R, Pulido D, de Haro C. Cloning and characterization of a cDNA encoding a protein synthesis initiation factor-2alpha (eIF-2alpha) kinase from Drosophila melanogaster. Homology To yeast GCN2 protein kinase. J Biol Chem. 1997 May 9;272(19):12544–12550. [PubMed]
  • Zhu S, Wek RC. Ribosome-binding domain of eukaryotic initiation factor-2 kinase GCN2 facilitates translation control. J Biol Chem. 1998 Jan 16;273(3):1808–1814. [PubMed]
  • Sikorski RS, Hieter P. A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics. 1989 May;122(1):19–27. [PMC free article] [PubMed]

Articles from Genetics are provided here courtesy of Genetics Society of America


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • Gene
    Gene links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene links
  • MedGen
    Related information in MedGen
  • Nucleotide
    Published Nucleotide sequences
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • Protein
    Published protein sequences
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links
  • Taxonomy
    Related taxonomy entry
  • Taxonomy Tree
    Taxonomy Tree

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...