Evolutionary engineering and molecular characterization of a caffeine-resistant Saccharomyces cerevisiae strain

  • Yusuf Sürmeli
  • Can Holyavkin
  • Alican Topaloğlu
  • Mevlüt Arslan
  • Halil İbrahim Kısakesen
  • Zeynep Petek ÇakarEmail author
Original Paper


Caffeine is a naturally occurring alkaloid, where its major consumption occurs with beverages such as coffee, soft drinks and tea. Despite a variety of reports on the effects of caffeine on diverse organisms including yeast, the complex molecular basis of caffeine resistance and response has yet to be understood. In this study, a caffeine-hyperresistant and genetically stable Saccharomyces cerevisiae mutant was obtained for the first time by evolutionary engineering, using batch selection in the presence of gradually increased caffeine stress levels and without any mutagenesis of the initial population prior to selection. The selected mutant could resist up to 50 mM caffeine, a level, to our knowledge, that has not been reported for S. cerevisiae so far. The mutant was also resistant to the cell wall-damaging agent lyticase, and it showed cross-resistance against various compounds such as rapamycin, antimycin, coniferyl aldehyde and cycloheximide. Comparative transcriptomic analysis results revealed that the genes involved in the energy conservation and production pathways, and pleiotropic drug resistance were overexpressed. Whole genome re-sequencing identified single nucleotide polymorphisms in only three genes of the caffeine-hyperresistant mutant; PDR1, PDR5 and RIM8, which may play a potential role in caffeine-hyperresistance.

Graphic abstract


Adaptive laboratory evolution Caffeine Evolutionary engineering Pleiotropic drug resistance (PDR) Saccharomyces cerevisiae Stress resistance 



We thank Levent Üge for technical assistance with HPLC analyses, and our former and present students Ogün Morkoç, Gizem Karabıyık, Diler Kaan Atmaca, and İsmail Can Karaoğlu for their help with the physiological experiments. We also thank Cihan Erdinç Gülsev and Nazlı Kocaefe for technical assistance with the whole genome re-sequencing experiments, Burcu Hacısalihoğlu for fruitful discussions and experimental assistance, Prof. Dr. Oğuz Öztürk for providing propolis and Prof. Dr. Nevin Gül Karagüler for her helpful comments regarding our SNP data.


The authors received no financial support for the research presented in this article.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11274_2019_2762_MOESM1_ESM.docx (20 kb)
Supplementary file1 (DOCX 20 kb)


  1. Adames NR, Gallegos JE, Peccoud J (2019) Yeast genetic interaction screens in the age of CRISPR/Cas. Curr Genet 65:307–327PubMedCrossRefGoogle Scholar
  2. Aguilar-Uscanga B, François J (2003) A study of the yeast cell wall composition and structure in response to growth conditions and mode of cultivation. Lett Appl Microbiol 37:268–274PubMedCrossRefGoogle Scholar
  3. Akache B, Turcotte B (2002) New regulators of drug sensitivity in the family of yeast zinc cluster proteins. J Biol Chem 277(24):21254–21260PubMedCrossRefGoogle Scholar
  4. Alkım C, Benbadis L, Yilmaz U, Cakar ZP, François JM (2013) Mechanisms other than activation of the iron regulon account for the hyper-resistance to cobalt of a Saccharomyces cerevisiae strain obtained by evolutionary engineering. Metallomics 5:1043–1060PubMedCrossRefGoogle Scholar
  5. Arslan M, Holyavkin C, Kısakesen HI, Topaloğlu A, Sürmeli Y, Çakar ZP (2018) Physiological and transcriptomic analysis of a chronologically long-lived Saccharomyces cerevisiae strain obtained by evolutionary engineering. Mol Biotechnol 60:468–474PubMedCrossRefGoogle Scholar
  6. Balzi E, Chen W, Ulaszewski S, Capieaux E, Goffeau A (1987) The multidrug resistance gene PDR1 from Saccharomyces cerevisiae. J Biol Chem 262(35):16871–16879PubMedGoogle Scholar
  7. Balzi E, Wang M, Leterme S, Van Dyck L, Goffeau A (1994) PDR5, a novel yeast multidrug resistance conferring transporter controlled by the transcription regulator PDR1. J Biol Chem 269(3):2206–2214PubMedGoogle Scholar
  8. Bentley NJ, Holtzman DA, Flaggs G, Keegan KS, DeMaggio A, Ford JC, Hoekstra M, Jarr AM (1996) The Schizosaccharomyces pombe rad3 checkpoint gene. EMBO J 15(23):6641–6651PubMedPubMedCentralCrossRefGoogle Scholar
  9. Blasina A, de Weyer IV, Laus MC, Luyten WH, Parker AE, McGowan CH (1999) A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Curr Biol 9(1):1–10PubMedCrossRefGoogle Scholar
  10. Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30:2114–2120PubMedPubMedCentralCrossRefGoogle Scholar
  11. Burke PV, Raitt DC, Allen LA, Kellogg EA, Poyton RO (1997) Effects of oxygen concentration on the expression of cytochrome c and cytochrome c oxidase genes in yeast. J Biol Chem 272(23):14705–14712PubMedCrossRefGoogle Scholar
  12. Çakar ZP, Seker UO, Tamerler C, Sonderegger M, Sauer U (2005) Evolutionary engineering of multiple-stress resistant Saccharomyces cerevisiae. FEMS Yeast Res 5:569–578PubMedCrossRefGoogle Scholar
  13. Çakar ZP, Alkım C, Turanlı B, Tokman N, Akman S, Sarıkaya M, Tamerler C, Benbadis L, Francois JM (2009) Isolation of cobalt hyper-resistant mutants of Saccharomyces cerevisiae by in vivo evolutionary engineering approach. J Biotechnol 143:130–138PubMedCrossRefGoogle Scholar
  14. Çakar ZP, Turanlı-Yıldız B, Alkım C, Yılmaz U (2012) Evolutionary engineering of Saccharomyces cerevisiae for improved industrially important properties. FEMS Yeast Res 12:171–182PubMedCrossRefGoogle Scholar
  15. Camandola S, Plick N, Mattson MP (2019) Impact of coffee and cacao purine metabolites on neuroplasticity and neurodegenerative disease. Neurochem Res 44:214–227PubMedCrossRefGoogle Scholar
  16. Carvajal E, van den Hazel HB, Cybularz-Kolaczkowska A, Balzi E, Goffeau A (1997) Molecular and phenotypic characterization of yeast PDR1 mutants that show hyperactive transcription of various ABC multidrug transporter genes. Mol Gen Genet 256(4):406–415PubMedCrossRefGoogle Scholar
  17. Castrejon F, Gomez A, Sanz M, Duran A, Roncero C (2006) The RIM101 pathway contributes to yeast cell wall assembly and its function becomes essential in the absence of mitogen-activated protein kinase Slt2p. Eukaryot Cell 5(3):507–517PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chen J-C, Hwang J-H (2016) Effects of caffeine on cell viability and activity of histone deacetylase 1 and histone acetyltransferase in glioma cells. Ci Ji Yi Xue Za Zhi 28(3):103–108PubMedPubMedCentralGoogle Scholar
  19. Cui Z, Shiraki T, Hirata D, Miyakawa T (1998) Yeast gene YRR1, which is required for resistance to 4-nitroquinoline N-oxide, mediates transcriptional activation of the multidrug resistance transporter gene SNQ2. Mol Microbiol 29(5):1307–1315PubMedCrossRefGoogle Scholar
  20. De Virgilio C, Loewith R (2006) Cell growth control: little eukaryotes make big contributions. Oncogene 25:6392–6415PubMedCrossRefGoogle Scholar
  21. De Castro PA, Savoldi M, Bonatto D, Malavazi I, Goldman MH, Berretta AA, Goldman GH (2012) Transcriptional profiling of Saccharomyces cerevisiae exposed to propolis. BMC Complement Altern Med 12:194PubMedPubMedCentralCrossRefGoogle Scholar
  22. Delaveau T, Delahodde A, Carvajal E, Subik J, Jacq C (1994) PDR3, a new yeast regulatory gene, is homologous to PDR1 and controls the multidrug resistance phenomenon. Mol Gen Genet 244(5):501–511PubMedCrossRefGoogle Scholar
  23. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, McKenna A, Fennell TJ, Kernytsky AM, Sivaschenko AY, Cibulskis K, Gabriel SB, Altshuler D, Daly MJ (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43:491–498PubMedPubMedCentralCrossRefGoogle Scholar
  24. DiCarlo JE, Norville JE, Mali P, Rios X, Aach J, Church GM (2013) Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems. Nucleic Acids Res 41:4336–4343PubMedPubMedCentralCrossRefGoogle Scholar
  25. Divate NR, Chen GH, Wang PM et al (2016) Engineering Saccharomyces cerevisiae for improvement in ethanol tolerance by accumulation of trehalose. Bioengineered 7:445–458PubMedPubMedCentralCrossRefGoogle Scholar
  26. Downes M, Mehla J, Ananthaswamy N, Wakschlag A, LaMonde M, Dine E, Ambudkar SV, Golin J (2013) The transmission interface of the Saccharomyces cerevisiae multidrug transporter Pdr5: Val-656 located in intracellular loop 2 plays a major role in drug resistance. Antimicrob Agents Chemother 57:1025–1034PubMedPubMedCentralCrossRefGoogle Scholar
  27. Egner R, Rosenthal FE, Kralli A, Sanglard D, Kuchler K (1998) Genetic separation of FK506 susceptibility and drug transport in the yeast Pdr5 ATP-binding cassette multidrug resistance transporter. Mol Biol Cell 9(2):523–543PubMedPubMedCentralCrossRefGoogle Scholar
  28. Entian KD, Kötter P (2007) Yeast genetic strain and plasmid collections. Methods Microbiol 36:629–666CrossRefGoogle Scholar
  29. Ferreira C, Silva S, van Voorst F, Aguiar C, Kielland-Brandt MC, Brandt A, Lucas C (2006) Absence of Gup1p in Saccharomyces cerevisiae results in defective cell wall composition, assembly, stability and morphology. FEMS Yeast Res 6(7):1027–1038PubMedCrossRefGoogle Scholar
  30. François J, Parrou JL (2001) Reserve carbohydrates metabolism in the yeast Saccharomyces cerevisiae. FEMS Microbiol Rev 25:125–145PubMedCrossRefGoogle Scholar
  31. Golin J, Ambudkar SV (2015) The multidrug transporter Pdr5 on the 25th anniversary of its discovery: an important model for the study of asymmetric ABC transporters. Biochem J 467(3):353–363PubMedPubMedCentralCrossRefGoogle Scholar
  32. Hacısalihoğlu B, Holyavkin C, Topaloğlu A, Kısakesen HI, Çakar ZP (2019) Genomic and transcriptomic analysis of a coniferyl aldehyde-resistant Saccharomyces cerevisiae strain obtained by evolutionary engineering. FEMS Yeast Res 19(3):foz021PubMedCrossRefGoogle Scholar
  33. Hardwick JS, Kuruvilla FG, Tong JK, Shamji AF, Schreiber SL (1999) Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc Natl Acad Sci 96:14866–14870PubMedCrossRefGoogle Scholar
  34. Hayashi M, Fukuzawa T, Sorimachi H, Maeda T (2005) Constitutive activation of the pH-responsive Rim101 pathway in yeast mutants defective in late steps of the MVB/ESCRT pathway. Mol Cell Biol 25(21):9478–9490PubMedPubMedCentralCrossRefGoogle Scholar
  35. Heckman MA, Weil J, De Mejia EG (2010) Caffeine (1,3,7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters. J Food Sci 75(3):77–87CrossRefGoogle Scholar
  36. Herrador A, Livas D, Soletto L, Becuwe M, Léon S, Vincent O (2015) Casein kinase 1 controls the activation threshold of an α-arrestin by multisite phosphorylation of the interdomain hinge. Mol Biol Cell 26(11):2128–2138PubMedPubMedCentralCrossRefGoogle Scholar
  37. Hood-DeGrenier JK (2011) Identification of phosphatase 2A-like Sit4-mediated signaling and ubiquitin-dependent protein sorting as modulators of caffeine sensitivity in S. cerevisiae. Yeast 28(3):189–204PubMedCrossRefGoogle Scholar
  38. James J (2004) Critical review of dietary caffeine and blood pressure: a relationship that should be taken more seriously. Psychosom Med 66(1):63–71PubMedCrossRefGoogle Scholar
  39. Johnston S, Zavortink M, Debouck C, Hopper J (1986) Functional domains of the yeast regulatory protein GAL4. Proc Natl Acad Sci 83:6553–6557PubMedCrossRefGoogle Scholar
  40. Katzmann DJ, Burnett PE, Golin J, Mahé Y, Moye-Rowley WS (1994) Transcriptional control of the yeast PDR5 gene by the PDR3 gene product. Mol Cell Biol 14(7):4653–4661PubMedPubMedCentralCrossRefGoogle Scholar
  41. Kihlman BA, Odmark G, Norlen K, Karlsson M-B (1971) Caffeine, caffeine derivatives and chromosomal aberrations, I. The relationship between ATP-concentration and the frequency of 8-ethoxy-caffeine-induced chromosomal exchanges in Vicia faba. Hereditas 68:291–304CrossRefGoogle Scholar
  42. Kolaczkowska A, Kolaczkowski M, Delahodde A, Goffeau A (2002) Functional dissection of Pdr1p, a regulator of multidrug resistance in Saccharomyces cerevisiae. Mol Genet Genomics 267:96–106PubMedCrossRefGoogle Scholar
  43. Kolaczkowski M, Kolaczowska A, Luczynski J, Witek S, Goffeau A (1998) In vivo characterization of the drug resistance profile of the major ABC transporters and other components of the yeast pleiotropic drug resistance network. Microb Drug Resist 4:143–158PubMedCrossRefGoogle Scholar
  44. Küçükgöze G, Alkım C, Yılmaz U, Kısakesen Hİ, Gündüz S, Akman S, Çakar ZP (2013) Evolutionary engineering and transcriptomic analysis of nickel-resistant Saccharomyces cerevisiae. FEMS Yeast Res 13:731–746PubMedCrossRefGoogle Scholar
  45. Kumar G, Keserwani S (2016) Mitotraumatism triggered by alkaloids (caffeine and nicotine) in root meristems of Lathyrus sativus L. (grass pea). Int J Res Bot 6(1):5–9Google Scholar
  46. Kuranda K, Leberre V, Sokol S, Palamarczyk G, François J (2006) Investigating the caffeine effects in the yeast Saccharomyces cerevisiae brings new insights into the connection between TOR, PKC and Ras/cAMP signaling pathways. Mol Microbiol 61(5):1147–1166PubMedCrossRefGoogle Scholar
  47. Lane S, Xu H, Oh EJ, Kim H, Lesmana A, Jeong D, Zhang G, Tsai C-S, Jin Y-S, Kim SR (2018) Glucose repression can be alleviated by reducing glucose phosphorylation rate in Saccharomyces cerevisiae. Sci Rep 8:2613PubMedPubMedCentralCrossRefGoogle Scholar
  48. Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760PubMedPubMedCentralCrossRefGoogle Scholar
  49. Li W, Mitchell AP (1997) Proteolytic activation of Rim1p, a positive regulator of yeast sporulation and invasive growth. Genetics 145:63–73PubMedPubMedCentralGoogle Scholar
  50. Ling H, Juwono NKP, Teo WS, Liu R, Leong SSJ, Chang MW (2015) Engineering transcription factors to improve tolerance against alkane biofuels in Saccharomyces cerevisiae. Biotechnol Biofuels 8:231PubMedPubMedCentralCrossRefGoogle Scholar
  51. Liu J, Barrientos A (2013) Transcriptional regulation of yeast oxidative phosphorylation hypoxic genes by oxidative stress. Antioxid Redox Signal 19(16):1916–1927PubMedPubMedCentralCrossRefGoogle Scholar
  52. Loewith R, Hall MN (2011) Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 189(4):1177–1201PubMedPubMedCentralCrossRefGoogle Scholar
  53. Lucau-Danila A, Delaveau T, Lelandais G, Devaux F, Jacq C (2003) Competitive promoter occupancy by two yeast paralogous transcription factors controlling the multidrug resistance phenomenon. J Biol Chem 278(52):52641–52650PubMedCrossRefGoogle Scholar
  54. Mahé Y, Lemoine Y, Kuchler K (1996) The ATP binding cassette transporters Pdr5 and Snq2 of Saccharomyces cerevisiae can mediate transport of steroids in vivo. J Biol Chem 271:25167–25172PubMedCrossRefGoogle Scholar
  55. Mamnun YM, Pandjaitan R, Mahé Y, Delahodde A, Kuchler K (2002) The yeast zinc finger regulators Pdr1p and Pdr3p control pleiotropic drug resistance (PDR) as homo- and heterodimers in vivo. Mol Microbiol 46(5):1429–1440PubMedCrossRefGoogle Scholar
  56. Mans R, Daran JMG, Pronk JT (2018) Under pressure: evolutionary engineering of yeast strains for improved performance in fuels and chemicals production. Curr Opinion Biotechnol 50:47–56CrossRefGoogle Scholar
  57. Marques MC, Zamarbide-Fores S, Pedelini L, Llopis-Torregrosa V, Yenush L (2015) A functional Rim101 complex is required for proper accumulation of the Ena1 Na+-ATPase protein in response to salt stress in Saccharomyces cerevisiae. FEMS Yeast Res 15(4):fov017PubMedCrossRefGoogle Scholar
  58. Matsui K, Teranishi S, Kamon S, Kuroda K, Ueda M (2008) Discovery of a modified transcription factor endowing yeasts with organic-solvent tolerance and reconstruction of an organic-solvent-tolerant Saccharomyces cerevisiae strain. J Appl Environ Microbiol 74(13):4222–4225CrossRefGoogle Scholar
  59. Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Simioni C, Leung E, Maclennan S, Baraldi PG, Borea PA (2007) Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1α, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. Mol Pharmacol 72(2):395–406PubMedCrossRefGoogle Scholar
  60. Mohanpuria P, Yadav SK (2009) Retardation in seedling growth and induction of early senescence in plants upon caffeine exposure is related to its negative effect on rubisco. Photosynthetica 47:293–297CrossRefGoogle Scholar
  61. Mohanpuria P, Kumar V, Yadav SK (2010) Tea caffeine: metabolism, functions and reduction strategies. Food Sci Biotechnol 19(2):275–287CrossRefGoogle Scholar
  62. Nehlig A, Debry G (1994) Potential genotoxic, mutagenic and antimutagenic effects of coffee: a review. Mutat Res 317(2):145–162PubMedCrossRefGoogle Scholar
  63. Nehlig A, Daval J-L, Debry G (1992) Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Rev 17:139–170PubMedCrossRefGoogle Scholar
  64. Nijkamp JF, von den Broek M, Datema E, de Kok S, Bosman L, Luttik MA, Daran-Lapujade P, Vongsangnak W, Nielsen J, Heijne WHM, Klaassen P, Paddon CJ, Platt D, Kötter P, van Ham RC, Reinders MJT, Pronk JT, de Ridder D, Daran J-M (2012) De novo sequencing, assembly, and analysis of the genome of the laboratory strain Saccharomyces cerevisiae CEN.PK113-7D, a model for modern industrial biotechnology. Microb Cell Fact 11:36PubMedPubMedCentralCrossRefGoogle Scholar
  65. Papapetridis I, Verhoeven MD, Wiersma SJ, Goudriaan M, van Maris AJA, Pronk JT (2018) Laboratory evolution for forced glucose-xylose co-consumption enables identification of mutations that improve mixed-sugar fermentation by xylose-fermenting Saccharomyces cerevisiae. FEMS Yeast Res 18:foy056PubMedCentralCrossRefPubMedGoogle Scholar
  66. Pennaneach V, Kolodner RD (2004) Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast. Nat Genet 36(6):612–617PubMedCrossRefGoogle Scholar
  67. Rallis C, Codlin S, Bähler J (2013) TORC1 signaling inhibition by rapamycin and caffeine affect lifespan, global gene expression, and cell proliferation of fission yeast. Aging Cell 12(4):563–573PubMedPubMedCentralCrossRefGoogle Scholar
  68. Raschmanova H, Weninger A, Glieder A, Kovar K, Vogl T (2018) Implementing CRISPR-Cas technologies in conventional and non-conventional yeasts: current state and future prospects. Biotechnol Adv 36:641–665PubMedCrossRefGoogle Scholar
  69. Reinke A, Chen J-C-Y, Aronova S, Powers T (2006) Caffeine targets TOR complex I and provides evidence for a regulatory link between the FRB and kinase domains of Tor1p. J Biol Chem 281(42):31616–31626PubMedCrossRefGoogle Scholar
  70. Ruepp A, Zollner A, Maier D, Albermann K, Hani J, Mokrejs M, Tetko I, Güldener U, Mannhaupt G, Münsterkötter M, Mewes HW (2004) The FunCat, a functional annotation scheme for systematic classification of proteins from whole genomes. Nucleic Acids Res 32:5539–5545PubMedPubMedCentralCrossRefGoogle Scholar
  71. Rutledge RM, Esser L, Ma J, Xia D (2011) Toward understanding the mechanism of action of the yeast multidrug resistance transporter Pdr5: a molecular modeling study. J Struct Biol 173:333–344PubMedCrossRefGoogle Scholar
  72. Sabisz M, Skladanowski A (2008) Modulation of cellular response to anticancer treatment by caffeine: inhibition of cell cycle checkpoints, DNA repair and more. Curr Pharm Biotechnol 9:325PubMedCrossRefGoogle Scholar
  73. Saiardi A, Resnick AC, Snowman AM, Wendland B, Snyder SH (2005) Inositol pyrophosphates regulate cell death and telomere length through phosphoinositide 3-kinase-related protein kinases. Proc Natl Acad Sci 102:1911–1914PubMedCrossRefGoogle Scholar
  74. Sanchez Y, Desany BA, Jones WJ, Liu Q, Wang B, Elledge SJ (1996) Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways. Science 271(5247):357–360PubMedCrossRefGoogle Scholar
  75. Sandlie I, Solberg K, Kleppe K (1980) The effect of caffeine on cell growth and metabolism of thymidine in Escherichia coli. Mutat Res 73:29–41PubMedCrossRefGoogle Scholar
  76. Sarkaria JN, Busby EC, Tibbetts RS, Roos P, Taya Y, Karnitz LM, Abraham RT (1999) Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res 59(17):4375–4382PubMedGoogle Scholar
  77. Sasamoto H, Fujii Y, Ashihara H (2015) Effect of purine alkaloids on the proliferation of lettuce cells derived from protoplasts. Nat Prod Commun 10(5):751–754PubMedGoogle Scholar
  78. Sauer U (2001) Evolutionary engineering of industrially important microbial phenotypes. Adv Biochem Eng Biotechnol 73:130–166Google Scholar
  79. Sauna ZE, Bohn SS, Rutledge R, Dougherty MP, Cronin S, May L, Xia D, Ambudkar SV, Golin J (2008) Mutations define cross-talk between the N-terminal nucleotide-binding domain and transmembrane helix-2 of the yeast multidrug transporter Pdr5: possible conservation of a signaling interface for coupling ATP hydrolysis to drug transport. J Biol Chem 283(50):35010–35022PubMedPubMedCentralCrossRefGoogle Scholar
  80. Schmitz H-P, Huppert S, Lorberg A, Heinisch JJ (2002) Rho5p downregulates the yeast cell integrity pathway. J Cell Sci 115:3139–3148PubMedGoogle Scholar
  81. Sinha RA, Farah BL, Singh BK, Siddique MM, Li Y, Wu Y, Ilkayeva OR, Gooding J, Ching J, Zhou J, Martinez L, Xie S, Bay B-H, Summers SA, Newgard CB, Yen PM (2014) Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice. Hepatology 59(4):1366–1380PubMedCrossRefGoogle Scholar
  82. Smardon AM, Kane PM (2014) Loss of vacuolar H+-ATPase activity in organelles signals ubiquitination and endocytosis of the yeast plasma membrane proton pump Pma1p. J Biol Chem 289(46):32316–32326PubMedPubMedCentralCrossRefGoogle Scholar
  83. Stovicek V, Holkenbrink C, Borodina I (2017) CRISPR/Cas system for yeast genome engineering: advances and applications. FEMS Yeast Res 17:fox030PubMedCentralCrossRefPubMedGoogle Scholar
  84. Sundström L, Larsson S, Jönsson LJ (2010) Identification of Saccharomyces cerevisiae genes involved in the resistance to phenolic fermentation inhibitors. Appl Biochem Biotechnol 161:106–115PubMedCrossRefGoogle Scholar
  85. Teixeira MC, Monteiro PT, Palma M, Costa C, Godinho CP, Pais P, Cavalheiro M, Antunes M, Lemos A, Pedreira T, Sá-Correia I (2018) YEASTRACT, an upgraded database for the analysis of transcription regulatory networks in Saccharomyces cerevisiae. Nucl Acids Res 46(D1):D348–D353PubMedCrossRefGoogle Scholar
  86. Tsujimoto Y, Shimizu Y, Otake K, Nakamura T, Okada R, Miyazaki T, Watanabe K (2015) Multidrug resistance transporters Snq2p and Pdr5p mediate caffeine efflux in Saccharomyces cerevisiae. Biosci Biotechnol Biochem 79(7):1103–1110PubMedCrossRefGoogle Scholar
  87. Turanlı-Yıldız B, Benbadis L, Alkım C, Sezgin T, Akşit A, Gökçe A, Öztürk Y, Baykal AT, Çakar ZP, François JM (2017) In vivo evolutionary engineering for ethanol-tolerance of Saccharomyces cerevisiae haploid cells triggers diploidization. J Biosci Bioeng 124(3):309–318PubMedCrossRefGoogle Scholar
  88. Velivela SD, Kane PM (2018) Compensatory internalization of Pma1 in V-ATPase mutants in Saccharomyces cerevisiae requires calcium- and glucose-sensitive phosphatases. Genetics 208(2):655–672PubMedCrossRefGoogle Scholar
  89. Vialard JE, Gilbert CS, Green CM, Lowndes NF (1998) The budding yeast Rad9 checkpoint protein is subjected to Mec1/Tel1-dependent hyperphosphorylation and interacts with Rad53 after DNA damage. EMBO J 17(19):5679–5688PubMedPubMedCentralCrossRefGoogle Scholar
  90. Wang Y, Kurihara Y, Sato T, Toh H, Kobayashi H, Sekiguchi T (2009) Gtr1p differentially associates with Gtr2p and Ego1p. Gene 437:32–38PubMedCrossRefGoogle Scholar
  91. Watcharawipas A, Watanabe D, Takagi H (2017) Enhanced sodium acetate tolerance in Saccharomyces cerevisiae by the Thr255Ala mutation of the ubiquitin ligase Rsp5. FEMS Yeast Res 17(8):fox083CrossRefGoogle Scholar
  92. Wolfger H, Mahé Y, Parle-McDermott A, Delahodde A, Kuchler K (1997) The yeast ATP binding cassette (ABC) protein genes PDR10 and PDR15 are novel targets for the Pdr1 and Pdr3 transcriptional regulators. FEBS Lett 418(3):269–274PubMedCrossRefGoogle Scholar
  93. Wright GA, Baker DD, Palmer MJ, Stabler D, Mustard JA, Power EF, Borland AM, Stevenson PC (2013) Caffeine in floral nectar enhances a pollinator’s memory of reward. Science 339:1202–1204PubMedPubMedCentralCrossRefGoogle Scholar
  94. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484CrossRefGoogle Scholar
  95. Xu X, Williams TC, Divne C, Pretorius IS, Paulsen IT (2019) Evolutionary engineering in Saccharomyces cerevisiae reveals a TRK1-dependent potassium influx mechanism for propionic acid tolerance. Biotechnol Biofuels 12:97PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Molecular Biology and Genetics, Faculty of Science & LettersIstanbul Technical UniversityIstanbulTurkey
  2. 2.Dr. Orhan Öcalgiray Molecular Biology, Biotechnology and Genetics Research Center (İTÜ-MOBGAM)Istanbul Technical UniversityIstanbulTurkey
  3. 3.Department of Agricultural Biotechnology, Faculty of AgricultureNamık Kemal UniversityTekirdağTurkey
  4. 4.Department of Genetics, Faculty of Veterinary MedicineVan Yüzüncü Yıl UniversityVanTurkey

Personalised recommendations