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The yeast VPS genes affect telomere length regulation

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Abstract

Eukaryotic cells invest a large proportion of their genome in maintaining telomere length homeostasis. Among the 173 non-essential yeast genes found to affect telomere length, a large proportion is involved in vacuolar traffic. When mutated, these vacuolar protein-sorting (VPS) genes lead to telomeres shorter than those observed in the wild type. Using genetic analysis, we characterized the pathway by which VPS15, VPS34, VPS22, VPS23 and VPS28 affect the telomeres. Our results indicate that these VPS genes affect telomere length through a single pathway and that this effect requires the activity of telomerase and the Ku heterodimer, but not the activity of Tel1p or Rif2p. We present models to explain the link between vacuolar traffic and telomere length homeostasis.

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References

  • Abeliovich H, Klionsky DJ (2001) Autophagy in yeast: mechanistic insights and physiological function. Microbiol Mol Biol Rev 65:463–479

    Article  CAS  PubMed  Google Scholar 

  • Askree SH, Yehuda T, Smolikov S, Gurevich R, Hawk J, Coker C, Krauskopf A, Kupiec M, McEachern MJ (2004) A genome-wide screen for Saccharomyces cerevisiae deletion mutants that affect telomere length. Proc Natl Acad Sci USA 101:8658–8663

    Article  CAS  PubMed  Google Scholar 

  • Babst M, Katzmann DJ, Estepa-Sabal EJ, Meerloo T, Emr SD (2002) Escrt-III an endosome-associated heterooligomeric protein complex required for mvb sorting. Dev Cell 3:271–282

    Article  CAS  PubMed  Google Scholar 

  • Babst M, Katzmann DJ, Snyder WB, Wendland B, Emr SD (2002) Endosome-associated complex, ESCRT-II, recruits transport machinery for protein sorting at the multivesicular body. Dev Cell 3:283–289

    Article  CAS  PubMed  Google Scholar 

  • Bennett CB, Lewis LK, Karthikeyan G, Lobachev KS, Jin YH, Sterling JF, Snipe JR, Resnick MA (2001) Genes required for ionizing radiation resistance in yeast. Nat Genet 29:426–434

    Article  CAS  PubMed  Google Scholar 

  • Bertuch AA, Lundblad V (2003) The Ku heterodimer performs separable activities at double-strand breaks and chromosome termini. Mol Cell Biol 23:8202–8215

    Article  CAS  PubMed  Google Scholar 

  • Bryant NJ, Piper RC, Gerrard SR, Stevens TH (1998) Traffic into the prevacuolar/endosomal compartment of Saccharomyces cerevisiae: a VPS45-dependent intracellular route and a VPS45-independent, endocytic route. Eur J Cell Biol 76:43–52

    CAS  PubMed  Google Scholar 

  • Budovskaya YV, Hama H, DeWald DB, Herman PK (2002) The C terminus of the Vps34p phosphoinositide 3-kinase is necessary and sufficient for the interaction with the Vps15p protein kinase. J Biol Chem 277:287–294

    Article  CAS  PubMed  Google Scholar 

  • Byrum J, Jordan S, Safrany ST, Rodgers W (2004) Visualization of inositol phosphate-dependent mobility of Ku: depletion of the DNA-PK cofactor InsP6 inhibits Ku mobility. Nucleic Acids Res 32:2776–2784

    Article  CAS  PubMed  Google Scholar 

  • Conibear E (2002) An ESCRT into the endosome. Mol Cell 10:215–216

    Article  CAS  PubMed  Google Scholar 

  • d’Adda di Fagagna F, Teo S-H, Jackson SP (2004) Functional links between telomeres and proteins of the DNA-damage response. Genes Dev 18:1781–1799

    Article  PubMed  Google Scholar 

  • D’Amours D, Jackson SP (2002) The Mre11 complex: at the crossroads of DNA repair and checkpoint signalling. Nat Rev Mol Cell Biol 3:317–327

    Article  CAS  PubMed  Google Scholar 

  • Evans SK, Lundblad V (2002) The Est1 subunit of Saccharomyces cerevisiae telomerase makes multiple contributions to telomere length maintenance. Genetics 162:1101–1115

    CAS  PubMed  Google Scholar 

  • Evans SK, Sistrunk ML, Nugent CI, Lundblad V (1998) Telomerase, Ku, and telomeric silencing in Saccharomyces cerevisiae. Chromosoma 107:352–358

    Article  CAS  PubMed  Google Scholar 

  • Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD (2001) Regulation of longevity and stress resistance by Sch9 in yeast. Science 292:288–290

    Article  CAS  PubMed  Google Scholar 

  • Ferreira MG, Miller KM, Cooper JP (2004) Indecent exposure: when telomeres become uncapped. Mol Cell 13:7–18

    Article  CAS  PubMed  Google Scholar 

  • Feuerbach F, Galy V, Trelles-Sticken E, Fromont-Racine M, Jacquier A, Gilson E, Olivo-Marin JC, Scherthan H, Nehrbass U (2002) Nuclear architecture and spatial positioning help establish transcriptional states of telomeres in yeast. Nat Cell Biol 4:214–221

    Article  CAS  PubMed  Google Scholar 

  • Fiorani P, Reid RJD, Schepis A, Jacquiau HR, Guo H, Thimmaiah P, Benedetti P, Bjornsti M-A (2004) The deubiquitinating enzyme Doa4p protects cells from DNA topoisomerase I poisons. J Biol Chem 279:21271–21281

    Article  CAS  PubMed  Google Scholar 

  • Giaever G, Chu AM, Ni L, Connelly C, Riles L, Veronneau S, Dow S, Lucau-Danila A, Anderson K, Andre B, Arkin AP, Astromoff A, El-Bakkoury M, Bangham R, Benito R, Brachat S, Campanaro S, Curtiss M, Davis K, Deutschbauer A, Entian KD, Flaherty P, Foury F, Garfinkel DJ, Gerstein M, Gotte D, Guldener U, Hegemann JH, Hempel S, Herman Z, Jaramillo DF, Kelly DE, Kelly SL, Kotter P, LaBonte D, Lamb DC, Lan N, Liang H, Liao H, Liu L, Luo C, Lussier M, Mao R, Menard P, Ooi SL, Revuelta JL, Roberts CJ, Rose M, Ross-Macdonald P, Scherens B, Schimmack G, Shafer B, Shoemaker DD, Sookhai-Mahadeo S, Storms RK, Strathern JN, Valle G, Voet M, Volckaert G, Wang CY, Ward TR, Wilhelmy J, Winzeler EA, Yang Y, Yen G, Youngman E, Yu K, Bussey H, Boeke JD, Snyder M, Philippsen P, Davis RW, Johnston M (2002) Functional profiling of the Saccharomyces cerevisiae genome. Nature 418:387–391

    Article  CAS  PubMed  Google Scholar 

  • Goldstein AL, McCusker JH (1999) Three new dominant drug resistance cassettes for gene disruption in Saccharomyces cerevisiae. Yeast 15:1541–1553

    Article  CAS  PubMed  Google Scholar 

  • Grandin N, Damon C, Charbonneau M (2000) Cdc13 cooperates with the yeast Ku proteins and Stn1 to regulate telomerase recruitment. Mol Cell Biol 20:8397–8408

    Article  CAS  PubMed  Google Scholar 

  • Gravel S, Wellinger RJ (2002) Maintenance of double-stranded telomeric repeats as the critical determinant for cell viability in yeast cells lacking Ku. Mol Cell Biol 22:2182–2193

    Article  CAS  PubMed  Google Scholar 

  • Gravel S, Larrivee M, Labrecque P, Wellinger RJ (1998) Yeast Ku as a regulator of chromosomal DNA end structure. Science 280:741–744

    Article  CAS  PubMed  Google Scholar 

  • Hanakahi LA, West SC (2002) Specific interaction of IP6 with human Ku70/80, the DNA-binding subunit of DNA-PK. EMBO J 21:2038–2044

    Article  CAS  PubMed  Google Scholar 

  • Hanakahi LA, Bartlet-Jones M, Chappell C, Pappin D, West SC (2000) Binding of inositol phosphate to DNA-PK and stimulation of double-strand break repair. Cell 102:721–729

    Article  CAS  PubMed  Google Scholar 

  • Hsu H-L, Gilley D, Galande SA, Hande MP, Allen B, Kim S-H, Li GC, Campisi J, Kohwi-Shigematsu T, Chen DJ (2000) Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev 14:2807–2812

    Article  CAS  PubMed  Google Scholar 

  • Jeon BW, Kim KT, Chang SI, Kim HY (2002) Phosphoinositide 3-OH kinase/protein kinase B inhibits apoptotic cell death induced by reactive oxygen species in Saccharomyces cerevisiae. J Biochem 131:693–699

    CAS  PubMed  Google Scholar 

  • Karlseder J, Hoke K, Mirzoeva OK, Bakkenist C, Kastan MB, Petrini JHJ, Lange TD (2004) The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response. PLS Biol 2:e240

    Google Scholar 

  • Katzmann DJ, Babst M, Emr SD (2001) Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 106:145–155

    Article  CAS  PubMed  Google Scholar 

  • Katzmann DJ, Stefan CJ, Babst M, Emr SD (2003) Vps27 recruits ESCRT machinery to endosomes during MVB sorting. J Cell Biol 162:413–423

    Article  CAS  PubMed  Google Scholar 

  • Kimura A, Ohmichi M, Kawagoe J, Kyo S, Mabuchi S, Takahashi T, Ohshima C, Arimoto-Ishida E, Nishio Y, Inoue M, Kurachi H, Tasaka K, Murata Y (2004) Induction of hTERT expression and phosphorylation by estrogen via Akt cascade in human ovarian cancer cell lines. Oncogene 23:4505–4515

    Article  CAS  PubMed  Google Scholar 

  • Li B, Warner JR (1996) Mutation of the Rab6 homologue of Saccharomyces cerevisiae, YPT6, inhibits both early Golgi function and ribosome biosynthesis. J Biol Chem 271:16813–16819

    Article  CAS  PubMed  Google Scholar 

  • Lundblad V, Blackburn EH (1993) An alternative pathway for yeast telomere maintenance rescues est1-senescence. Cell 73:347–360

    Article  CAS  PubMed  Google Scholar 

  • Marston AL, Tham W-H, Shah H, Amon A (2004) A genome-wide screen identifies genes required for centromeric cohesion. Science 303:1367–1370

    Article  CAS  PubMed  Google Scholar 

  • Martin TF (1998) Phosphoinositide lipids as signaling molecules: common themes for signal transduction, cytoskeletal regulation, and membrane trafficking. Annu Rev Cell Dev Biol 14:231–264

    Article  CAS  PubMed  Google Scholar 

  • Matteis MAD, Godi A (2004) PI-loting membrane traffic. Nat Cell Biol 6:487–492

    Article  PubMed  Google Scholar 

  • Matynia A, Salus SS, Sazer S (2002) Three proteins required for early steps in the protein secretory pathway also affect nuclear envelope structure and cell cycle progression in fission yeast. J Cell Sci 115:421–431

    CAS  PubMed  Google Scholar 

  • McEachern MJ, Krauskopf A, Blackburn EH (2000) Telomeres and their control. Annu Rev Genet 34:331–358

    Article  CAS  PubMed  Google Scholar 

  • Nugent CI, Bosco G, Ross LO, Evans SK, Salinger AP, Moore JK, Haber JE, Lundblad V (1998) Telomere maintenance is dependent on activities required for end repair of double-strand breaks. Curr Biol 8:657–662

    Article  CAS  PubMed  Google Scholar 

  • Odorizzi G, Katzmann DJ, Babst M, Audhya A, Emr SD (2003) Bro1 is an endosome-associated protein that functions in the MVB pathway in Saccharomyces cerevisiae. J Cell Sci 116:1893–1903

    Article  CAS  PubMed  Google Scholar 

  • Olovnikov AM (1973) A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 41:181–190

    CAS  PubMed  Google Scholar 

  • Pina B, Fernandez-Larrea J, Garcia-Reyero N, Idrissi FZ (2003) The different (sur)faces of Rap1p. Mol Genet Genomics 268:791–798

    CAS  PubMed  Google Scholar 

  • Polotnianka RM, Li J, Lustig AJ (1998) The yeast Ku heterodimer is essential for protection of the telomere against nucleolytic and recombinational activities. Curr Biol 8:831–834

    Article  CAS  PubMed  Google Scholar 

  • Raymond CK, Howald-Stevenson I, Vater CA, Stevens TH (1992) Morphological classification of the yeast vacuolar protein sorting mutants: evidence for a prevacuolar compartment in class E vps mutants. Mol Biol Cell 3:1389–1402

    CAS  PubMed  Google Scholar 

  • Ritchie KB, Mallory JC, Petes TD (1999) Interactions of TLC1 (which encodes the RNA subunit of telomerase), TEL1, and MEC1 in regulating telomere length in the yeast Saccharomyces cerevisiae. Mol Cell Biol 19:6065–6075

    CAS  PubMed  Google Scholar 

  • Roberts P, Moshitch-Moshkovitz S, Kvam E, O’Toole E, Winey M, Goldfarb DS (2003) Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae. Mol Biol Cell 14:129–141

    Article  CAS  PubMed  Google Scholar 

  • Rouse J, Jackson SP (2002) Interfaces between the detection, signaling, and repair of DNA damage. Science 297:547–551

    Article  CAS  PubMed  Google Scholar 

  • Ryan KJ, Wente SR (2002) Isolation and characterization of new Saccharomyces cerevisiae mutants perturbed in nuclear pore complex assembly. Genetics 3:17

    PubMed  Google Scholar 

  • 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 271:357–360

    CAS  PubMed  Google Scholar 

  • Scheid MP, Woodgett JR (2003) Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett 546:108–112

    Article  CAS  PubMed  Google Scholar 

  • Shampay J, Blackburn EH (1988) Generation of telomere-length heterogeneity in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 85:534–538

    CAS  PubMed  Google Scholar 

  • Smogorzewska A, de Lange T (2004) Regulation of telomerase by telomeric proteins. Annu Rev Biochem (in press)

  • Smolikov S, Krauskopf A (2003) The Rap1p-telomere complex does not determine the replicative capacity of telomerase-deficient yeast. Mol Cell Biol 23:8729–8739

    Article  CAS  PubMed  Google Scholar 

  • Stellwagen AE, Haimberger ZW, Veatch JR, Gottschling DE (2003) Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends. Genes Dev 17:2384–2395

    Article  CAS  PubMed  Google Scholar 

  • Teixeira MT, Dujon B, Fabre E (2002) Genome-wide nuclear morphology screen identifies novel genes involved in nuclear architecture and gene-silencing in Saccharomyces cerevisiae. J Mol Biol 321:551–561

    Article  CAS  PubMed  Google Scholar 

  • Teo SH, Jackson SP (2001) Telomerase subunit overexpression suppresses telomere-specific checkpoint activation in the yeast yku80 mutant. EMBO Rep 2:197–202

    Article  CAS  PubMed  Google Scholar 

  • Teter SA, Klionsky DJ (2000) Transport of proteins to the yeast vacuole: autophagy, cytoplasm-to-vacuole targeting, and role of the vacuole in degradation. Semin Cell Dev Biol 11:173–179

    Article  CAS  PubMed  Google Scholar 

  • Thorpe GW, Fong CS, Alic N, Higgins VJ, Dawes IW (2004) Cells have distinct mechanisms to maintain protection against different reactive oxygen species: oxidative-stress-response genes. Proc Natl Acad Sci USA 101:6564–6569

    Article  CAS  PubMed  Google Scholar 

  • Vincent K, Wang Q, Jay S, Hobbs K, Rymond BC (2003) Genetic interactions with CLF1 identify additional pre-mRNA splicing factors and a link between activators of yeast vesicular transport and splicing. Genetics 164:895–907

    CAS  PubMed  Google Scholar 

  • Wotton D, Shore D (1997) A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae. Genes Dev 11:748–760

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Y. Mazor, T. Yehuda, H. Maddar and R. Gurevich for their help and support. This work was supported by grants from the Israel Science Foundation (A.K., M.K.) and the Israeli Ministry of Health (M.K.).

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Correspondence to Martin Kupiec.

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Communicated by S. Hohmann

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Rog, O., Smolikov, S., Krauskopf, A. et al. The yeast VPS genes affect telomere length regulation. Curr Genet 47, 18–28 (2005). https://doi.org/10.1007/s00294-004-0548-y

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