Studies in fission yeast have previously identified evolutionarily conserved shelterin and Stn1-Ten1 complexes, and established Rad3ATR/Tel1ATM-dependent phosphorylation of the shelterin subunit Ccq1 at Thr93 as the critical post-translational modification for telomerase recruitment to telomeres. Furthermore, shelterin subunits Poz1, Rap1 and Taz1 have been identified as negative regulators of Thr93 phosphorylation and telomerase recruitment. However, it remained unclear how telomere maintenance is dynamically regulated during the cell cycle. Thus, we investigated how loss of Poz1, Rap1 and Taz1 affects cell cycle regulation of Ccq1 Thr93 phosphorylation and telomere association of telomerase (Trt1TERT), DNA polymerases, Replication Protein A (RPA) complex, Rad3ATR-Rad26ATRIP checkpoint kinase complex, Tel1ATM kinase, shelterin subunits (Tpz1, Ccq1 and Poz1) and Stn1. We further investigated how telomere shortening, caused by trt1Δ or catalytically dead Trt1-D743A, affects cell cycle-regulated telomere association of telomerase and DNA polymerases. These analyses established that fission yeast shelterin maintains telomere length homeostasis by coordinating the differential arrival of leading (Polε) and lagging (Polα) strand DNA polymerases at telomeres to modulate Rad3ATR association, Ccq1 Thr93 phosphorylation and telomerase recruitment.
Vyšlo v časopise: Fission Yeast Shelterin Regulates DNA Polymerases and Rad3 Kinase to Limit Telomere Extension. PLoS Genet 9(11): e32767. doi:10.1371/journal.pgen.1003936 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003936
1. VerdunRE, KarlsederJ (2007) Replication and protection of telomeres. Nature 447 : 924–931.
2. GilsonE, GeliV (2007) How telomeres are replicated. Nat Rev Mol Cell Biol 8 : 825–838.
3. BlackburnEH, GreiderCW, SzostakJW (2006) Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 12 : 1133–1138.
4. PalmW, de LangeT (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42 : 301–334.
5. ArmaniosM, BlackburnEH (2012) The telomere syndromes. Nat Rev Genet 13 : 693–704.
6. MiyoshiT, KanohJ, SaitoM, IshikawaF (2008) Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length. Science 320 : 1341–1344.
7. MoserBA, NakamuraTM (2009) Protection and replication of telomeres in fission yeast. Biochem Cell Biol 87 : 747–758.
8. KanohJ, IshikawaF (2001) spRap1 and spRif1, recruited to telomeres by Taz1, are essential for telomere function in fission yeast. Curr Biol 11 : 1624–1630.
9. TomitaK, CooperJP (2008) Fission yeast Ccq1 is telomerase recruiter and local checkpoint controller. Genes Dev 22 : 3461–3474.
10. MoserBA, ChangYT, KostiJ, NakamuraTM (2011) Tel1ATM and Rad3ATR kinases promote Ccq1-Est1 interaction to maintain telomeres in fission yeast. Nat Struct Mol Biol 18 : 1408–1413.
11. NaitoT, MatsuuraA, IshikawaF (1998) Circular chromosome formation in a fission yeast mutant defective in two ATM homologues. Nat Genet 20 : 203–206.
12. MoserBA, SubramanianL, KhairL, ChangYT, NakamuraTM (2009) Fission yeast Tel1ATM and Rad3ATR promote telomere protection and telomerase recruitment. PLoS Genet 5: e1000622.
13. YamazakiH, TarumotoY, IshikawaF (2012) Tel1ATM and Rad3ATR phosphorylate the telomere protein Ccq1 to recruit telomerase and elongate telomeres in fission yeast. Genes Dev 26 : 241–246.
14. MiyakeY, NakamuraM, NabetaniA, ShimamuraS, TamuraM, et al. (2009) RPA-like mammalian Ctc1-Stn1-Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway. Mol Cell 36 : 193–206.
15. SurovtsevaYV, ChurikovD, BoltzKA, SongX, LambJC, et al. (2009) Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes. Mol Cell 36 : 207–218.
16. PriceCM, BoltzKA, ChaikenMF, StewartJA, BeilsteinMA, et al. (2010) Evolution of CST function in telomere maintenance. Cell Cycle 9 : 3157–3165.
17. CasteelDE, ZhuangS, ZengY, PerrinoFW, BossGR, et al. (2009) A DNA polymerase-α•primase cofactor with homology to replication protein A-32 regulates DNA replication in mammalian cells. J Biol Chem 284 : 5807–5818.
18. PuglisiA, BianchiA, LemmensL, DamayP, ShoreD (2008) Distinct roles for yeast Stn1 in telomere capping and telomerase inhibition. EMBO J 27 : 2328–2339.
19. QiH, ZakianVA (2000) The Saccharomyces telomere-binding protein Cdc13p interacts with both the catalytic subunit of DNA polymerase α and the telomerase-associated Est1 protein. Genes Dev 14 : 1777–1788.
20. WangF, StewartJA, KasbekC, ZhaoY, WrightWE, et al. (2012) Human CST has independent functions during telomere duplex replication and C-strand fill-in. Cell Rep 2 : 1096–1103.
21. WuP, TakaiH, de LangeT (2012) Telomeric 3′ overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell 150 : 39–52.
22. NakaokaH, NishiyamaA, SaitoM, IshikawaF (2012) Xenopus laevis Ctc1-Stn1-Ten1 (xCST) protein complex is involved in priming DNA synthesis on single-stranded DNA template in Xenopus egg extract. J Biol Chem 287 : 619–627.
23. ChenLY, RedonS, LingnerJ (2012) The human CST complex is a terminator of telomerase activity. Nature 488 : 540–544.
24. MartinV, DuLL, RozenzhakS, RussellP (2007) Protection of telomeres by a conserved Stn1-Ten1 complex. Proc Natl Acad Sci U S A 104 : 14038–14043.
25. MoserBA, SubramanianL, ChangYT, NoguchiC, NoguchiE, et al. (2009) Differential arrival of leading and lagging strand DNA polymerases at fission yeast telomeres. EMBO J 28 : 810–820.
26. MillerKM, RogO, CooperJP (2006) Semi-conservative DNA replication through telomeres requires Taz1. Nature 440 : 824–828.
27. SfeirA, KosiyatrakulST, HockemeyerD, MacRaeSL, KarlsederJ, et al. (2009) Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell 138 : 90–103.
28. MillerKM, FerreiraMG, CooperJP (2005) Taz1, Rap1 and Rif1 act both interdependently and independently to maintain telomeres. EMBO J 24 : 3128–3135.
29. ChikashigeY, HiraokaY (2001) Telomere binding of the Rap1 protein is required for meiosis in fission yeast. Curr Biol 11 : 1618–1623.
30. KhairL, SubramanianL, MoserBA, NakamuraTM (2009) Roles of heterochromatin and telomere proteins in regulation of fission yeast telomere recombination and telomerase recruitment. J Biol Chem 285 : 5327–5337.
31. FerreiraMG, CooperJP (2001) The fission yeast Taz1 protein protects chromosomes from Ku-dependent end-to-end fusions. Mol Cell 7 : 55–63.
32. FujitaI, TanakaM, KanohJ (2012) Identification of the functional domains of the telomere protein Rap1 in Schizosaccharomyces pombe. PLoS One 7: e49151.
33. TazumiA, FukuuraM, NakatoR, KishimotoA, TakenakaT, et al. (2012) Telomere-binding protein Taz1 controls global replication timing through its localization near late replication origins in fission yeast. Genes Dev 26 : 2050–2062.
34. DehePM, RogO, FerreiraMG, GreenwoodJ, CooperJP (2012) Taz1 enforces cell-cycle regulation of telomere synthesis. Mol Cell 46 : 797–808.
35. WanM, QinJ, SongyangZ, LiuD (2009) OB fold-containing protein 1 (OBFC1), a human homolog of yeast Stn1, associates with TPP1 and is implicated in telomere length regulation. J Biol Chem 284 : 26725–26731.
36. CooperJP, NimmoER, AllshireRC, CechTR (1997) Regulation of telomere length and function by a Myb-domain protein in fission yeast. Nature 385 : 744–747.
37. TomaskaL, WillcoxS, SlezakovaJ, NosekJ, GriffithJD (2004) Taz1 binding to a fission yeast model telomere: formation of telomeric loops and higher order structures. J Biol Chem 279 : 50764–50772.
38. HaeringCH, NakamuraTM, BaumannP, CechTR (2000) Analysis of telomerase catalytic subunit mutants in vivo and in vitro in Schizosaccharomycespombe. Proc Natl Acad Sci U S A 97 : 6367–6372.
39. de LangeT (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19 : 2100–2110.
40. ChenY, RaiR, ZhouZR, KanohJ, RibeyreC, et al. (2011) A conserved motif within RAP1 has diversified roles in telomere protection and regulation in different organisms. Nat Struct Mol Biol 18 : 213–221.
41. MillerKM, CooperJP (2003) The telomere protein Taz1 is required to prevent and repair genomic DNA breaks. Mol Cell 11 : 303–313.
42. HayanoM, KanohY, MatsumotoS, Renard-GuilletC, ShirahigeK, et al. (2012) Rif1 is a global regulator of timing of replication origin firing in fission yeast. Genes Dev 26 : 137–150.
43. BianchiA, ShoreD (2007) Early replication of short telomeres in budding yeast. Cell 128 : 1051–1062.
44. ArnoultN, Schluth-BolardC, LetessierA, DrascovicI, Bouarich-BourimiR, et al. (2010) Replication timing of human telomeres is chromosome arm-specific, influenced by subtelomeric structures and connected to nuclear localization. PLoS Genet 6: e1000920.
45. VerdunRE, CrabbeL, HaggblomC, KarlsederJ (2005) Functional human telomeres are recognized as DNA damage in G2 of the cell cycle. Mol Cell 20 : 551–561.
46. YamazakiS, IshiiA, KanohY, OdaM, NishitoY, et al. (2012) Rif1 regulates the replication timing domains on the human genome. EMBO J 31 : 3667–3677.
47. CornacchiaD, DileepV, QuivyJP, FotiR, TiliF, et al. (2012) Mouse Rif1 is a key regulator of the replication-timing programme in mammalian cells. EMBO J 31 : 3678–3690.
48. DahlenM, SunnerhagenP, WangTS (2003) Replication proteins influence the maintenance of telomere length and telomerase protein stability. Mol Cell Biol 23 : 3031–3042.
49. Adams-MartinA, DionneI, WellingerRJ, HolmC (2000) The function of DNA polymerase alpha at telomeric G tails is important for telomere homeostasis. Mol Cell Biol 20 : 786–796.
50. OhyaT, KawasakiY, HiragaS, KanbaraS, NakajoK, et al. (2002) The DNA polymerase domain of polε is required for rapid, efficient, and highly accurate chromosomal DNA replication, telomere length maintenance, and normal cell senescence in Saccharomyces cerevisiae. J Biol Chem 277 : 28099–28108.
51. ZhaoY, SfeirAJ, ZouY, BusemanCM, ChowTT, et al. (2009) Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells. Cell 138 : 463–475.
52. Alfa C, Fantes P, Hyams J, McLoed M, Warbrick E (1993) Experiments with Fission Yeast. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
53. NakamuraTM, MoserBA, RussellP (2002) Telomere binding of checkpoint sensor and DNA repair proteins contributes to maintenance of functional fission yeast telomeres. Genetics 161 : 1437–1452.
54. NakamuraTM, MorinGB, ChapmanKB, WeinrichSL, AndrewsWH, et al. (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 277 : 955–959.
55. WachA, BrachatA, PohlmannR, PhilippsenP (1994) New heterologous modules for classical or PCR-based gene disruptions in Saccharomyces cerevisiae. Yeast 10 : 1793–1808.
56. BentleyNJ, HoltzmanDA, FlaggsG, KeeganKS, DeMaggioA, et al. (1996) The Schizosaccharomyces pombe rad3 checkpoint gene. EMBO J 15 : 6641–6651.
57. SubramanianL, NakamuraTM (2010) A kinase-independent role for the Rad3ATR-Rad26ATRIP complex in recruitment of Tel1ATM to telomeres in fission yeast. PLoS Genet 6: e1000839.
58. WebbCJ, ZakianVA (2008) Identification and characterization of the Schizosaccharomyces pombe TER1 telomerase RNA. Nat Struct Mol Biol 15 : 34–42.
59. NoguchiE, NoguchiC, McDonaldWH, YatesJR (2004) Swi1 and Swi3 are components of a replication fork protection complex in fission yeast. Mol Cell Biol 24 : 8342–8355.
60. HodsonJA, BailisJM, ForsburgSL (2003) Efficient labeling of fission yeast Schizosaccharomyces pombe with thymidine and BUdR. Nucleic Acids Res 31: e134.
61. SubramanianL, MoserBA, NakamuraTM (2008) Recombination-based telomere maintenance is dependent on Tel1-MRN and Rap1 and inhibited by telomerase, Taz1, and Ku in fission yeast. Mol Cell Biol 28 : 1443–1455.
62. NakamuraTM, CooperJP, CechTR (1998) Two modes of survival of fission yeast without telomerase. Science 282 : 493–496.
63. KanohJ, SadaieM, UranoT, IshikawaF (2005) Telomere binding protein Taz1 establishes Swi6 heterochromatin independently of RNAi at telomeres. Curr Biol 15 : 1808–1819.
64. HayashiM, KatouY, ItohT, TazumiA, YamadaY, et al. (2007) Genome-wide localization of pre-RC sites and identification of replication origins in fission yeast. EMBO J 26 : 1327–1339.
65. SivakumarS, Porter-GoffM, PatelPK, BenoitK, RhindN (2004) In vivo labeling of fission yeast DNA with thymidine and thymidine analogs. Methods 33 : 213–219.
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