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Gene Review

DFR1  -  dihydrofolate reductase

Saccharomyces cerevisiae S288c

Synonyms: Dihydrofolate reductase, O5231, YOR236W
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Disease relevance of DFR1


High impact information on DFR1

  • The efficiency of refolding of a tester protein, dihydrofolate reductase, was significantly reduced in mitochondria lacking Mdj1p after incubation at elevated temperature [4].
  • Our data argue against this model: import intermediates of cytochromes c1 and b2 were found only outside the inner membrane; maturation of these proteins was independent of the matrix-localized hsp60 chaperone; and dihydrofolate reductase linked to the presequence of either cytochrome was imported to the intermembrane space in the absence of ATP [5].
  • Using a positive/negative selection protocol, we demonstrated that the efficiency of targeting into DHFR genes is indistinguishable in normal and amplified CHO cells [6].
  • Arg-DHFR, a dihydrofolate reductase bearing an amino-terminal (N-terminal) arginine, is long-lived in the yeast Saccharomyces cerevisiae, even though arginine is a destabilizing residue in the N-end rule of protein degradation [7].
  • In vitro, Hsp60 bound to DHFR in the course of thermal denaturation, preventing its aggregation, and mediated its adenosine triphosphate-dependent refolding at increased temperatures [8].

Biological context of DFR1

  • Nucleotide sequence analysis revealed that the yeast DFR1 gene encoded a polypeptide with a predicted Mr of 24230 [9].
  • We also mapped the DFR1 gene to a position 1.4 cM proximal to the MET7 locus on chromosome XV [9].
  • The upstream region contains two consensus sequences required for binding of the yeast's positive regulatory factor, GCN4, suggesting that the DFR1 gene might be subject to the amino acid general control [9].
  • These results, particularly for DFR1, are in marked contrast with those obtained in other eukaryotic systems which have suggested that, in general, genes encoding enzymes involved in DNA precursor synthesis are subject to cell cycle regulation [10].
  • Amplification of a circular episome carrying an inverted repeat of the DFR1 locus and adjacent autonomously replicating sequence element of Saccharomyces cerevisiae [11].

Anatomical context of DFR1


Associations of DFR1 with chemical compounds

  • We report here the detailed structure of a DFR1 episome amplified in methotrexate-resistant strain 25-1 [11].
  • The inability of the mutants to metabolize FA suggests that the DFR1 gene product may have a role in folate metabolism in addition to its well-characterized function in the reduction of dihydrofolate [15].
  • This result is surprising, as yeast cells treated with MTX are expected to be phenocopies of dfr1 mutants [15].
  • In order to overcome this lack of respiratory activity in the dfr1 mutants, we isolated strains containing a dominant mutation, DIR, which allows growth on glycerol in the presence of antifolate drugs [15].
  • However, unlike wt strains treated with MTX, the growth requirements of the dfr1 mutant are not satisfied by exogenous 5-formyltetrahydrofolic acid (FA; folinic acid) in complex (YEPD) medium [15].

Regulatory relationships of DFR1


Other interactions of DFR1


Analytical, diagnostic and therapeutic context of DFR1

  • We tested this possibility by measuring gene targeting in normal CHO cells with two copies of the dihydrofolate reductase (DHFR) gene and in amplified CHOC 400 cells, which carry 800 copies [6].
  • We used PCR mutagenesis, screened >1000 DHFR alleles that encoded functional enzymes and studied approximately 100 that were more resistant than a naturally occurring resistant allele (N51I and S108N) [22].
  • Sequence analysis of resistant mutants obtained in the presence of sulfa drugs showed no changes in DHFR, or DHPS, unlike previously found antifolate-resistant mutants.The diamino derivatives, which are precursors of the sulfa-DHP, were found to be DHFR inhibitors [23].
  • Inhibitors of dihydrofolate reductase (DHFR) have been a mainstay of chemotherapy of falciparum malaria for >50 years [22].


  1. Molecular characterization of the Saccharomyces cerevisiae dihydrofolate reductase gene (DFR1). Lagosky, P.A., Taylor, G.R., Haynes, R.H. Nucleic Acids Res. (1987) [Pubmed]
  2. In vitro generation of novel pyrimethamine resistance mutations in the Toxoplasma gondii dihydrofolate reductase. Reynolds, M.G., Oh, J., Roos, D.S. Antimicrob. Agents Chemother. (2001) [Pubmed]
  3. Identification of the optimal third generation antifolate against P. falciparum and P. vivax. Hunt, S.Y., Detering, C., Varani, G., Jacobus, D.P., Schiehser, G.A., Shieh, H.M., Nevchas, I., Terpinski, J., Sibley, C.H. Mol. Biochem. Parasitol. (2005) [Pubmed]
  4. Mdj1p, a novel chaperone of the DnaJ family, is involved in mitochondrial biogenesis and protein folding. Rowley, N., Prip-Buus, C., Westermann, B., Brown, C., Schwarz, E., Barrell, B., Neupert, W. Cell (1994) [Pubmed]
  5. Cytochromes c1 and b2 are sorted to the intermembrane space of yeast mitochondria by a stop-transfer mechanism. Glick, B.S., Brandt, A., Cunningham, K., Müller, S., Hallberg, R.L., Schatz, G. Cell (1992) [Pubmed]
  6. Gene targeting in normal and amplified cell lines. Zheng, H., Wilson, J.H. Nature (1990) [Pubmed]
  7. Heat-inducible degron: a method for constructing temperature-sensitive mutants. Dohmen, R.J., Wu, P., Varshavsky, A. Science (1994) [Pubmed]
  8. Prevention of protein denaturation under heat stress by the chaperonin Hsp60. Martin, J., Horwich, A.L., Hartl, F.U. Science (1992) [Pubmed]
  9. Mapping and sequencing of the dihydrofolate reductase gene (DFR1) of Saccharomyces cerevisiae. Barclay, B.J., Huang, T., Nagel, M.G., Misener, V.L., Game, J.C., Wahl, G.M. Gene (1988) [Pubmed]
  10. Transcription of genes encoding enzymes involved in DNA synthesis during the cell cycle of Saccharomyces cerevisiae. McIntosh, E.M., Gadsden, M.H., Haynes, R.H. Mol. Gen. Genet. (1986) [Pubmed]
  11. Amplification of a circular episome carrying an inverted repeat of the DFR1 locus and adjacent autonomously replicating sequence element of Saccharomyces cerevisiae. Huang, T., Campbell, J.L. J. Biol. Chem. (1995) [Pubmed]
  12. An internal region of the peroxisomal membrane protein PMP47 is essential for sorting to peroxisomes. McCammon, M.T., McNew, J.A., Willy, P.J., Goodman, J.M. J. Cell Biol. (1994) [Pubmed]
  13. Import of a DHFR hybrid protein into glycosomes in vivo is not inhibited by the folate-analogue aminopterin. Häusler, T., Stierhof, Y.D., Wirtz, E., Clayton, C. J. Cell Biol. (1996) [Pubmed]
  14. Protein folding causes an arrest of preprotein translocation into mitochondria in vivo. Wienhues, U., Becker, K., Schleyer, M., Guiard, B., Tropschug, M., Horwich, A.L., Pfanner, N., Neupert, W. J. Cell Biol. (1991) [Pubmed]
  15. The phenotype of a dihydrofolate reductase mutant of Saccharomyces cerevisiae. Huang, T., Barclay, B.J., Kalman, T.I., von Borstel, R.C., Hastings, P.J. Gene (1992) [Pubmed]
  16. Expression of plasmid R388-encoded type II dihydrofolate reductase as a dominant selective marker in Saccharomyces cerevisiae. Miyajima, A., Miyajima, I., Arai, K., Arai, N. Mol. Cell. Biol. (1984) [Pubmed]
  17. Hsp60-independent protein folding in the matrix of yeast mitochondria. Rospert, S., Looser, R., Dubaquie, Y., Matouschek, A., Glick, B.S., Schatz, G. EMBO J. (1996) [Pubmed]
  18. Sequence of a dihydrofolate reductase-encoding gene from Candida albicans. Daly, S., Mastromei, G., Yacoub, A., Lorenzetti, R. Gene (1994) [Pubmed]
  19. Subcellular locations of MOD5 proteins: mapping of sequences sufficient for targeting to mitochondria and demonstration that mitochondrial and nuclear isoforms commingle in the cytosol. Boguta, M., Hunter, L.A., Shen, W.C., Gillman, E.C., Martin, N.C., Hopper, A.K. Mol. Cell. Biol. (1994) [Pubmed]
  20. Analysis of nucleo-cytoplasmic transport in a thermosensitive mutant of nuclear pore protein NSP1. Nehrbass, U., Fabre, E., Dihlmann, S., Herth, W., Hurt, E.C. Eur. J. Cell Biol. (1993) [Pubmed]
  21. Influence of the nuclear gene tmp3 on the loss of mitochondrial genes in Saccharomyces cerevisiae. Zelikson, R., Luzzati, M. Mol. Cell. Biol. (1982) [Pubmed]
  22. Mutagenesis of dihydrofolate reductase from Plasmodium falciparum: analysis in Saccharomyces cerevisiae of triple mutant alleles resistant to pyrimethamine or WR99210. Ferlan, J.T., Mookherjee, S., Okezie, I.N., Fulgence, L., Sibley, C.H. Mol. Biochem. Parasitol. (2001) [Pubmed]
  23. Inhibition studies of sulfonamide-containing folate analogs in yeast. Patel, O., Satchell, J., Baell, J., Fernley, R., Coloe, P., Macreadie, I. Microb. Drug Resist. (2003) [Pubmed]
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