Environmental Stresses Disrupt Telomere Length Homeostasis

English version České info

Telomeres protect the chromosome ends from degradation and play crucial roles in cellular aging and disease. Recent studies have additionally found a correlation between psychological stress, telomere length, and health outcome in humans. However, studies have not yet explored the causal relationship between stress and telomere length, or the molecular mechanisms underlying that relationship. Using yeast as a model organism, we show that stresses may have very different outcomes: alcohol and acetic acid elongate telomeres, whereas caffeine and high temperatures shorten telomeres. Additional treatments, such as oxidative stress, show no effect. By combining genome-wide expression measurements with a systematic genetic screen, we identify the Rap1/Rif1 pathway as the central mediator of the telomeric response to environmental signals. These results demonstrate that telomere length can be manipulated, and that a carefully regulated homeostasis may become markedly deregulated in opposing directions in response to different environmental cues.

Vyšlo v časopise: Environmental Stresses Disrupt Telomere Length Homeostasis. PLoS Genet 9(9): e32767. doi:10.1371/journal.pgen.1003721
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003721

Souhrn

Zdroje

1. ChanSW, BlackburnEH (2002) New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin. Oncogene 21: 553–563.

2. de LangeT (2009) How telomeres solve the end-protection problem. Science 326: 948–952.

3. CollinsK, MitchellJR (2002) Telomerase in the human organism. Oncogene 21: 564–579.

4. HayflickL (1965) The Limited in Vitro Lifetime of Human Diploid Cell Strains. Exp Cell Res 37: 614–636.

5. LundbladV, SzostakJW (1989) A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57: 633–643.

6. BlascoMA (2005) Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6: 611–622.

7. BakaysaSL, MucciLA, SlagboomPE, BoomsmaDI, McClearnGE, et al. (2007) Telomere length predicts survival independent of genetic influences. Aging Cell 6: 769–774.

8. JaskelioffM, MullerFL, PaikJH, ThomasE, JiangS, et al. (2010) Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469: 102–106.

9. AskreeSH, YehudaT, SmolikovS, GurevichR, HawkJ, et al. (2004) A genome-wide screen for Saccharomyces cerevisiae deletion mutants that affect telomere length. Proc Natl Acad Sci U S A 101: 8658–8663.

10. GatbontonT, ImbesiM, NelsonM, AkeyJM, RuderferDM, et al. (2006) Telomere length as a quantitative trait: genome-wide survey and genetic mapping of telomere length-control genes in yeast. PLoS Genet 2: e35.

11. UngarL, YosefN, SelaY, SharanR, RuppinE, et al. (2009) A genome-wide screen for essential yeast genes that affect telomere length maintenance. Nucleic Acids Res 37: 3840–3849.

12. ShacharR, UngarL, KupiecM, RuppinE, SharanR (2008) A systems-level approach to mapping the telomere length maintenance gene circuitry. Mol Syst Biol 4: 172.

13. YosefN, UngarL, ZalckvarE, KimchiA, KupiecM, et al. (2009) Toward accurate reconstruction of functional protein networks. Mol Syst Biol 5: 248.

14. DamjanovicAK, YangY, GlaserR, Kiecolt-GlaserJK, NguyenH, et al. (2007) Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer's disease patients. J Immunol 179: 4249–4254.

15. EpelES, LinJ, DhabharFS, WolkowitzOM, PutermanE, et al. (2010) Dynamics of telomerase activity in response to acute psychological stress. Brain, behavior, and immunity 24: 531–539.

16. ChangM, ArnericM, LingnerJ (2007) Telomerase repeat addition processivity is increased at critically short telomeres in a Tel1-dependent manner in Saccharomyces cerevisiae. Genes Dev 21: 2485–2494.

17. TusherVG, TibshiraniR, ChuG (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98: 5116–5121.

18. GaschAP, SpellmanPT, KaoCM, Carmel-HarelO, EisenMB, et al. (2000) Genomic expression programs in the response of yeast cells to environmental changes. Mol Biol Cell 11: 4241–4257.

19. GiaeverG, ChuAM, NiL, ConnellyC, RilesL, et al. (2002) Functional profiling of the Saccharomyces cerevisiae genome. Nature 418: 387–391.

20. BreslowDK, CameronDM, CollinsSR, SchuldinerM, Stewart-OrnsteinJ, et al. (2008) A comprehensive strategy enabling high-resolution functional analysis of the yeast genome. Nat Methods 5: 711–718.

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

22. KyrionG, BoakyeKA, LustigAJ (1992) C-terminal truncation of RAP1 results in the deregulation of telomere size, stability, and function in Saccharomyces cerevisiae. Mol Cell Biol 12: 5159–5173.

23. KrauskopfA, BlackburnEH (1998) Rap1 protein regulates telomere turnover in yeast. Proceedings of the National Academy of Sciences of the United States of America 95: 12486–12491.

24. StanleyD, ChambersPJ, StanleyGA, BornemanA, FraserS (2010) Transcriptional changes associated with ethanol tolerance in Saccharomyces cerevisiae. Applied microbiology and biotechnology 88: 231–239.

25. DavierwalaAP, HaynesJ, LiZ, BrostRL, RobinsonMD, et al. (2005) The synthetic genetic interaction spectrum of essential genes. Nat Genet 37: 1147–1152.

26. HayanoM, KanohY, MatsumotoS, Renard-GuilletC, ShirahigeK, et al. (2012) Rif1 is a global regulator of timing of replication origin firing in fission yeast. Genes & development 26: 137–150.

27. ParkS, PattersonEE, CobbJ, AudhyaA, GartenbergMR, et al. (2011) Palmitoylation controls the dynamics of budding-yeast heterochromatin via the telomere-binding protein Rif1. Proceedings of the National Academy of Sciences of the United States of America 108: 14572–14577.

28. MartinaM, ClericiM, BaldoV, BonettiD, LucchiniG, et al. (2012) A Balance between Tel1 and Rif2 Activities Regulates Nucleolytic Processing and Elongation at Telomeres. Mol Cell Biol 32: 1604–1617.

29. McGeeJS, PhillipsJA, ChanA, SabourinM, PaeschkeK, et al. (2010) Reduced Rif2 and lack of Mec1 target short telomeres for elongation rather than double-strand break repair. Nature structural & molecular biology 17: 1438–1445.

30. RibeyreC, ShoreD (2012) Anticheckpoint pathways at telomeres in yeast. Nature structural & molecular biology 19: 307–313.

31. XueY, RushtonMD, MaringeleL (2011) A novel checkpoint and RPA inhibitory pathway regulated by Rif1. PLoS Genet 7: e1002417.

32. AnbalaganS, BonettiD, LucchiniG, LongheseMP (2011) Rif1 supports the function of the CST complex in yeast telomere capping. PLoS Genet 7: e1002024.

33. ArnericM, LingnerJ (2007) Tel1 kinase and subtelomere-bound Tbf1 mediate preferential elongation of short telomeres by telomerase in yeast. EMBO Rep 8: 1080–1085.

34. TsukamotoY, TaggartAK, ZakianVA (2001) The role of the Mre11-Rad50-Xrs2 complex in telomerase- mediated lengthening of Saccharomyces cerevisiae telomeres. Current biology : CB 11: 1328–1335.

35. NugentCI, BoscoG, RossLO, EvansSK, SalingerAP, et al. (1998) Telomere maintenance is dependent on activities required for end repair of double-strand breaks. Current biology : CB 8: 657–660.

36. GrandinN, ReedSI, CharbonneauM (1997) Stn1, a new Saccharomyces cerevisiae protein, is implicated in telomere size regulation in association with Cdc13. Genes & development 11: 512–527.

37. LewJE, EnomotoS, BermanJ (1998) Telomere length regulation and telomeric chromatin require the nonsense-mediated mRNA decay pathway. Mol Cell Biol 18: 6121–6130.

38. AddinallSG, HolsteinEM, LawlessC, YuM, ChapmanK, et al. (2011) Quantitative fitness analysis shows that NMD proteins and many other protein complexes suppress or enhance distinct telomere cap defects. PLoS genetics 7: e1001362.

39. AmerikA, SindhiN, HochstrasserM (2006) A conserved late endosome-targeting signal required for Doa4 deubiquitylating enzyme function. The Journal of cell biology 175: 825–835.

40. RogO, SmolikovS, KrauskopfA, KupiecM (2005) The yeast VPS genes affect telomere length regulation. Current genetics 47: 18–28.

41. YuTY, WangCY, LinJJ (2012) Depleting Components of the THO Complex Causes Increased Telomere Length by Reducing the Expression of the Telomere-Associated Protein Rif1p. PloS one 7: e33498.

42. HalfmannR, JaroszDF, JonesSK, ChangA, LancasterAK, et al. (2012) Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature 482: 363–368.

43. SarkariaJN, BusbyEC, TibbettsRS, RoosP, TayaY, et al. (1999) Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res 59: 4375–4382.

44. SaiardiA, ResnickAC, SnowmanAM, WendlandB, SnyderSH (2005) Inositol pyrophosphates regulate cell death and telomere length through phosphoinositide 3-kinase-related protein kinases. Proc Natl Acad Sci U S A 102: 1911–1914.

45. TakataH, KanohY, GungeN, ShirahigeK, MatsuuraA (2004) Reciprocal association of the budding yeast ATM-related proteins Tel1 and Mec1 with telomeres in vivo. Mol Cell 14: 515–522.

46. PaschiniM, ToroTB, LubinJW, Braunstein-BallewB, MorrisDK, et al. (2012) A Naturally Thermolabile Activity Compromises Genetic Analysis of Telomere Function in Saccharomyces cerevisiae. Genetics 191: 79–93.

47. BlascoMA (2007) Telomere length, stem cells and aging. Nature chemical biology 3: 640–649.

48. ArtandiSE, DePinhoRA (2010) Telomeres and telomerase in cancer. Carcinogenesis 31: 9–18.

49. EpelES, BlackburnEH, LinJ, DhabharFS, AdlerNE, et al. (2004) Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A 101: 17312–17315.

50. NeedhamBL, FernandezJR, LinJ, EpelES, BlackburnEH (2012) Socioeconomic status and cell aging in children. Soc Sci Med 74: 1948–51.

51. DuM, PrescottJ, KraftP, HanJ, GiovannucciE, et al. (2012) Physical activity, sedentary behavior, and leukocyte telomere length in women. Am J Epidemiol 175: 414–422.

52. McCulleyJL, PetesTD (2010) Chromosome rearrangements and aneuploidy in yeast strains lacking both Tel1p and Mec1p reflect deficiencies in two different mechanisms. Proceedings of the National Academy of Sciences of the United States of America 107: 11465–11470.

53. UngarL, HarariY, TorenA, KupiecM (2011) Tor complex 1 controls telomere length by affecting the level of Ku. Current biology : CB 21: 2115–2120.

54. HochreiterS, ClevertDA, ObermayerK (2006) A new summarization method for Affymetrix probe level data. Bioinformatics 22: 943–949.

55. Knorr EM, Ng RT. A unified approach for mining outliers; 1997. IBM Press. pp. 11.

56. BraunsteinM, RoseAB, HolmesSG, AllisCD, BroachJR (1993) Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev 7: 592–604.

57. FisherTS, TaggartAK, ZakianVA (2004) Cell cycle-dependent regulation of yeast telomerase by Ku. Nat Struct Mol Biol 11: 1198–1205.