Telomerase Is Required for Zebrafish Lifespan

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Telomerase activity is restricted in humans. Consequentially, telomeres shorten in most cells throughout our lives. Telomere dysfunction in vertebrates has been primarily studied in inbred mice strains with very long telomeres that fail to deplete telomeric repeats during their lifetime. It is, therefore, unclear how telomere shortening regulates tissue homeostasis in vertebrates with naturally short telomeres. Zebrafish have restricted telomerase expression and human-like telomere length. Here we show that first-generation tert^−/− zebrafish die prematurely with shorter telomeres. tert^−/− fish develop degenerative phenotypes, including premature infertility, gastrointestinal atrophy, and sarcopaenia. tert^−/− mutants have impaired cell proliferation, accumulation of DNA damage markers, and a p53 response leading to early apoptosis, followed by accumulation of senescent cells. Apoptosis is primarily observed in the proliferative niche and germ cells. Cell proliferation, but not apoptosis, is rescued in tp53^−/−tert^−/− mutants, underscoring p53 as mediator of telomerase deficiency and consequent telomere instability. Thus, telomerase is limiting for zebrafish lifespan, enabling the study of telomere shortening in naturally ageing individuals.

Vyšlo v časopise: Telomerase Is Required for Zebrafish Lifespan. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003214
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003214

Souhrn

Zdroje

1. de LangeT (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19: 2100–2110.

2. LevyMZ, AllsoppRC, FutcherAB, GreiderCW, HarleyCB (1992) Telomere end-replication problem and cell aging. J Mol Biol 225: 951–960.

3. d'Adda di FagagnaF, ReaperPM, Clay-FarraceL, FieglerH, CarrP, et al. (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426: 194–198.

4. GreiderCW, BlackburnEH (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43: 405–413.

5. GreiderCW, BlackburnEH (1989) A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337: 331–337.

6. ForsythNR, WrightWE, ShayJW (2002) Telomerase and differentiation in multicellular organisms: turn it off, turn it on, and turn it off again. Differentiation 69: 188–197.

7. KarlsederJ, SmogorzewskaA, de LangeT (2002) Senescence induced by altered telomere state, not telomere loss. Science 295: 2446–2449.

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

9. CampisiJ, SedivyJ (2009) How does proliferative homeostasis change with age? What causes it and how does it contribute to aging? J Gerontol A Biol Sci Med Sci 64: 164–166.

10. HoferAC, TranRT, AzizOZ, WrightW, NovelliG, et al. (2005) Shared phenotypes among segmental progeroid syndromes suggest underlying pathways of aging. J Gerontol A Biol Sci Med Sci 60: 10–20.

11. AlterBP, RosenbergPS, GiriN, BaerlocherGM, LansdorpPM, et al. (2012) Telomere length is associated with disease severity and declines with age in dyskeratosis congenita. Haematologica 97: 353–359.

12. FerreiraMG, MillerKM, CooperJP (2004) Indecent exposure: when telomeres become uncapped. Mol Cell 13: 7–18.

13. SahinE, DepinhoRA (2010) Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464: 520–528.

14. RoosWP, KainaB (2006) DNA damage-induced cell death by apoptosis. Trends Mol Med 12: 440–450.

15. ManningEL, CrosslandJ, DeweyMJ, Van ZantG (2002) Influences of inbreeding and genetics on telomere length in mice. Mamm Genome 13: 234–238.

16. BlascoMA, LeeHW, HandeMP, SamperE, LansdorpPM, et al. (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91: 25–34.

17. RudolphKL, ChangS, LeeHW, BlascoM, GottliebGJ, et al. (1999) Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96: 701–712.

18. ErdmannN, LiuY, HarringtonL (2004) Distinct dosage requirements for the maintenance of long and short telomeres in mTert heterozygous mice. Proc Natl Acad Sci U S A 101: 6080–6085.

19. ChoudhuryAR, JuZ, DjojosubrotoMW, SchienkeA, LechelA, et al. (2007) Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 39: 99–105.

20. ArtandiSE, AttardiLD (2005) Pathways connecting telomeres and p53 in senescence, apoptosis, and cancer. Biochem Biophys Res Commun 331: 881–890.

21. SperkaT, SongZ, MoritaY, NalapareddyK, GuachallaLM, et al. (2012) Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction. Nat Cell Biol 14: 73–79.

22. ArmaniosM, AlderJK, ParryEM, KarimB, StrongMA, et al. (2009) Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Genet 85: 823–832.

23. ElmoreLW, NorrisMW, SircarS, BrightAT, McChesneyPA, et al. (2008) Upregulation of telomerase function during tissue regeneration. Exp Biol Med (Maywood) 233: 958–967.

24. AnchelinM, MurciaL, Alcaraz-PerezF, Garcia-NavarroEM, CayuelaML (2011) Behaviour of telomere and telomerase during aging and regeneration in zebrafish. PLoS ONE 6: e16955 doi:10.1371/journal.pone.0016955.

25. KishiS, BaylissPE, UchiyamaJ, KoshimizuE, QiJ, et al. (2008) The identification of zebrafish mutants showing alterations in senescence-associated biomarkers. PLoS Genet 4: e1000152 doi:10.1371/journal.pgen.1000152.

26. WienholdsE, van EedenF, KostersM, MuddeJ, PlasterkRH, et al. (2003) Efficient target-selected mutagenesis in zebrafish. Genome Res 13: 2700–2707.

27. KimNW, PiatyszekMA, ProwseKR, HarleyCB, WestMD, et al. (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266: 2011–2015.

28. ThomasDR (2007) Loss of skeletal muscle mass in aging: examining the relationship of starvation, sarcopenia and cachexia. Clin Nutr 26: 389–399.

29. LiewWC, BartfaiR, LimZ, SreenivasanR, SiegfriedKR, et al. (2012) Polygenic sex determination system in zebrafish. PLoS ONE 7: e34397 doi:10.1371/journal.pone.0034397.

30. LeeHW, BlascoMA, GottliebGJ, HornerJW2nd, GreiderCW, et al. (1998) Essential role of mouse telomerase in proliferative organs. Nature 392: 569–574.

31. GrierHJ, LintonJR, LeatherlandJF, De VlamingVL (1980) Structural evidence for two different testicular types in teleost fishes. Am J Anat 159: 331–345.

32. MeznikovaM, ErdmannN, AllsoppR, HarringtonLA (2009) Telomerase reverse transcriptase-dependent telomere equilibration mitigates tissue dysfunction in mTert heterozygotes. Dis Model Mech 2: 620–626.

33. Tomas-LobaA, FloresI, Fernandez-MarcosPJ, CayuelaML, MaraverA, et al. (2008) Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135: 609–622.

34. JaskelioffM, MullerFL, PaikJH, ThomasE, JiangS, et al. (2011) Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469: 102–106.

35. Bernardes de JesusB, VeraE, SchneebergerK, TejeraAM, AyusoE, et al. (2012) Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med

36. OzakiY, SaitoK, ShinyaM, KawasakiT, SakaiN (2011) Evaluation of Sycp3, Plzf and Cyclin B3 expression and suitability as spermatogonia and spermatocyte markers in zebrafish. Gene Expr Patterns 11: 309–315.

37. HemannMT, RudolphKL, StrongMA, DePinhoRA, ChinL, et al. (2001) Telomere dysfunction triggers developmentally regulated germ cell apoptosis. Mol Biol Cell 12: 2023–2030.

38. SharplessNE, DePinhoRA (2007) How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8: 703–713.

39. HewittG, JurkD, MarquesFD, Correia-MeloC, HardyT, et al. (2012) Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun 3: 708.

40. FumagalliM, RossielloF, ClericiM, BarozziS, CittaroD, et al. (2012) Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol 14: 355–365.

41. DavidsonAJ, ZonLI (2004) The ‘definitive’ (and ‘primitive’) guide to zebrafish hematopoiesis. Oncogene 23: 7233–7246.

42. SalminenA, OjalaJ, KaarnirantaK (2011) Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cell Mol Life Sci 68: 1021–1031.

43. DanilovaN, KumagaiA, LinJ (2010) p53 upregulation is a frequent response to deficiency of cell-essential genes. PLoS ONE 5: e15938 doi:10.1371/journal.pone.0015938.

44. ChinL, ArtandiSE, ShenQ, TamA, LeeSL, et al. (1999) p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97: 527–538.

45. BerghmansS, MurpheyRD, WienholdsE, NeubergD, KutokJL, et al. (2005) tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors. Proc Natl Acad Sci U S A 102: 407–412.

46. WrightWE, ShayJW (2000) Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nat Med 6: 849–851.

47. AubertG, LansdorpPM (2008) Telomeres and aging. Physiol Rev 88: 557–579.

48. FloresI, BlascoMA (2009) A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres. PLoS ONE 4: e4934 doi:10.1371/journal.pone.0004934.

49. WienholdsE, PlasterkRH (2004) Target-selected gene inactivation in zebrafish. Methods Cell Biol 77: 69–90.

50. KimuraM, StoneRC, HuntSC, SkurnickJ, LuX, et al. (2010) Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths. Nat Protoc 5: 1596–1607.

51. RogO, MillerKM, FerreiraMG, CooperJP (2009) Sumoylation of RecQ helicase controls the fate of dysfunctional telomeres. Mol Cell 33: 559–569.