#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Nur1 Dephosphorylation Confers Positive Feedback to Mitotic Exit Phosphatase Activation in Budding Yeast


During the cell cycle, a specific sequence of events leads to the formation of two daughter cells from one mother cell. Progression through the cell cycle is tightly controlled, with events occurring in the right place at the right time. Exactly how this is achieved is still being elucidated. In budding yeast, the events occurring during the final cell cycle phase – “mitotic exit” – are controlled by the phosphatase Cdc14. It is kept sequestered and inactive until it is needed for mitotic exit, at which time it is rapidly released. In this study, we have identified a new regulator of Cdc14 activity, the protein Nur1. In a series of experiments, we saw that Nur1 acts both upstream and downstream of Cdc14 activation, thereby creating a positive feedback loop. On the one hand, Nur1 contributes to inhibiting Cdc14 until the start of mitotic exit. On the other hand, through the actions of Cdc14 itself, Nur1 is disabled as an opponent of the phosphatase. This creates a robust system, rapidly switching between two opposing states and thus driving forward the mitotic exit transition.


Vyšlo v časopise: Nur1 Dephosphorylation Confers Positive Feedback to Mitotic Exit Phosphatase Activation in Budding Yeast. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004907
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004907

Souhrn

During the cell cycle, a specific sequence of events leads to the formation of two daughter cells from one mother cell. Progression through the cell cycle is tightly controlled, with events occurring in the right place at the right time. Exactly how this is achieved is still being elucidated. In budding yeast, the events occurring during the final cell cycle phase – “mitotic exit” – are controlled by the phosphatase Cdc14. It is kept sequestered and inactive until it is needed for mitotic exit, at which time it is rapidly released. In this study, we have identified a new regulator of Cdc14 activity, the protein Nur1. In a series of experiments, we saw that Nur1 acts both upstream and downstream of Cdc14 activation, thereby creating a positive feedback loop. On the one hand, Nur1 contributes to inhibiting Cdc14 until the start of mitotic exit. On the other hand, through the actions of Cdc14 itself, Nur1 is disabled as an opponent of the phosphatase. This creates a robust system, rapidly switching between two opposing states and thus driving forward the mitotic exit transition.


Zdroje

1. Morgan D (2007) The cell cycle: Principles of control. London: New Science Press.

2. UhlmannF, BouchouxC, López-AvilésS (2011) A quantitative model for cyclin-dependent kinase control of the cell cycle: revisited. Phil Trans R Soc B 366: 3572–3583.

3. VisintinR, CraigK, HwangES, PrinzS, TyersM, et al. (1998) The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation. Mol Cell 2: 709–718.

4. BouchouxC, UhlmannF (2011) A quantitative model for ordered Cdk substrate dephosphorylation during mitotic exit. Cell 147: 803–814.

5. PereiraG, SchiebelE (2003) Separase regulates INCENP-Aurora B anaphase spindle function through Cdc14. Science 302: 2120–2124.

6. HiguchiT, UhlmannF (2005) Stabilization of microtubule dynamics at anaphase onset promotes chromosome segregation. Nature 433: 171–176.

7. WoodburyEL, MorganDO (2007) Cdk and APC activities limit the spindle-stabilizing function of Fin1 to anaphase. Nat Cell Biol 9: 106–112.

8. KhmelinskiiA, RoostaluJ, RoqueH, AntonyC, SchiebelE (2009) Phosphorylation-dependent protein interactions at the spindle midzone mediate cell cycle regulation of spindle elongation. Dev Cell 17: 244–256.

9. MirchenkoL, UhlmannF (2010) Sli15INCENP dephosphorylation prevents mitotic checkpoint reengagement due to loss of tension at anaphase onset. Curr Biol 20: 1396–1401.

10. ZachariaeW, SchwabM, NasmythK, SeufertW (1998) Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex. Science 282: 1721–1724.

11. JaspersenSL, CharlesJF, MorganDO (1999) Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14. Curr Biol 9: 227–236.

12. ShouW, SeolJH, ShevchenkoA, BaskervilleC, MoazedD, et al. (1999) Exit from mitosis is triggered by Tem1-dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex. Cell 97: 233–244.

13. VisintinR, HwangES, AmonA (1999) Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus. Nature 398: 818–823.

14. TraversoEE, BaskervilleC, LiuY-X, ShouW, JamesP, et al. (2001) Characterization of the Net1 cell cycle-dependent regulator of the Cdc14 phosphatase from budding yeast. J Biol Chem 276: 21924–21931.

15. ShouW, AzzamR, ChenSL, HuddlestonMJ, BaskervilleC, et al. (2002) Cdc5 influences phosphorylation of Net1 and disassembly of the RENT complex. BMC Mol Biol 3: 3.

16. YoshidaS, Toh-eA (2002) Budding yeast Cdc5 phosphorylates Net1 and assists Cdc14 release from the nucleolus. Biochem Biophys Res Commun 294: 687–691.

17. AzzamR, ChenSL, ShouW, MahAS, AlexandruG, et al. (2004) Phosphorylation by cyclin B-Cdk underlies release of mitotic exit activator Cdc14 from the nucleolus. Science 305: 516–519.

18. SullivanM, UhlmannF (2003) A non-proteolytic function of separase links the onset of anaphase to mitotic exit. Nat Cell Biol 5: 249–254.

19. QueraltE, LehaneC, NovakB, UhlmannF (2006) Downregulation of PP2ACdc55 phosphatase by separase initiates mitotic exit in budding yeast. Cell 125: 719–732.

20. StegmeierF, VisintinR, AmonA (2002) Separase, polo kinase, the kinetochore protein Slk19, and Spo12 function in a network that controls Cdc14 localization during early anaphase. Cell 108: 207–220.

21. JaspersenSL, CharlesJF, Tinker-KulbergRL, MorganDO (1998) A late mitotic regulatory network controlling cyclin destruction in Saccharomyces cerevisiae. Mol Biol Cell 9: 2803–2817.

22. FesquetD, FitzpatrickPJ, JohnsonAL, KramerKM, ToynJH, et al. (1999) A Bub2p-dependent spindle checkpoint pathway regulates the Dbf2p kinase in budding yeast. EMBO J 18: 2424–2434.

23. LeeSE, FrenzLM, WellsNJ, JohnsonAL, JohnstonLH (2001) Order of function of the budding yeast mitotic exit-network proteins Tem1, Cdc15, Mob1, Dbf2, and Cdc5. Curr Biol 11: 784–788.

24. MahAS, JangJ, DeshaiesRJ (2001) Protein kinase Cdc15 activates the Dbf2-Mob1 kinase complex. Proc Natl Acad Sci USA 98: 7325–7330.

25. JaspersenSL, MorganDO (2000) Cdc14 activates Cdc15 to promote mitotic exit in budding yeast. Curr Biol 10: 615–618.

26. KönigC, MaekawaH, SchiebelE (2010) Mutual regulation of cyclin-dependent kinase and the mitotic exit network. J Cell Biol 188: 351–368.

27. SullivanM, HiguchiT, KatisVL, UhlmannF (2004) Cdc14 phosphatase induces rDNA condensation and resolves cohesin-independent cohesion during budding yeast anaphase. Cell 117: 471–482.

28. D'AmoursD, StegmeierF, AmonA (2004) Cdc14 and condensin control the dissolution of cohesin-independent linkages at repeated DNA. Cell 117: 455–469.

29. WangB-D, Yong-GonzalezV, StrunnikovAV (2004) Cdc14p/FEAR pathway controls segregation of nucleolus in S. cerevisiae by facilitating condensin targeting to rDNA chromatin in anaphase. Cell Cycle 3: 960–967.

30. D'AmbrosioC, KellyG, ShirahigeK, UhlmannF (2008) Condensin-dependent rDNA decatenation introduces a temporal pattern to chromosome segregation. Curr Biol 18: 1084–1089.

31. WangB-D, ButylinP, StrunnikovA (2006) Condensin function in mitotic nucleolar segregation is regulated by rDNA transcription. Cell Cycle 5: 2260–2267.

32. TomsonBN, D'AmoursD, AdamsonBS, AragonL, AmonA (2006) Ribosomal DNA transcription-dependent processes interfere with chromosome segregation. Mol Cell Biol 26: 6239–6247.

33. ElliottSG, McLaughlinCS (1979) Regulation of RNA synthesis in yeast III. Mol Gen Genet 169: 237–243.

34. Kuilman T, Maiolica A, Scheidel N, Aebersold R, Uhlmann F (2014) Identification of Cdk targets that control cytokinesis. EMBO J. epub ahead of print: DOI10.15252/embj.201488958.

35. KingMC, LuskCP, BlobelG (2006) Karyopherin-mediated import of integral inner nuclear membrane proteins. Nature 442: 1003–1007.

36. MekhailK, SeebacherJ, GygiSP, MoazedD (2008) Role for perinuclear chromosome tethering in maintenance of genome stability. Nature 456: 667–670.

37. ChanJN, PoonBP, SalviJ, OlsenJB, EmiliA, et al. (2011) Perinuclear cohibin complexes maintain replicative life span via roles at distinct silent chromatin domains. Dev Cell 20: 867–879.

38. Holt LJ, Tuch BB, Villén J, Johnson AD, Gygi SP, et al. (2009) Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution. Science 325.

39. CulottiJ, HartwellLH (1971) Genetic control of the cell division cycle in yeast. III. Seven genes controlling nuclear division. Exp Cell Res 67: 389–401.

40. LyonsNA, MorganDO (2011) Cdk1-dependent destruction of Eco1 prevents cohesion establishment after S phase. Mol Cell 42: 378–389.

41. DefossezPA, PrustyR, KaeberleinM, LinSJ, FerrignoP, et al. (1999) Elimination of replication block protein Fob1 extends the life span of yeast mother cells. Mol Cell 3: 447–455.

42. StegmeierF, AmonA (2004) Closing mitosis: The functions of the Cdc14 phosphatase and its regulation. Annu Rev Genet 38: 203–231.

43. ShouW, SakamotoKM, KeenerJ, MorimotoKW, TraversoEE, et al. (2001) Net1 stimulates RNA polymerase I transcription and regulates nucleolar structure independently of controlling mitotic exit. Mol Cell 8: 45–55.

44. RabitschKP, PetronczkiM, JaverzatJ-P, GenierS, ChwallaB, et al. (2003) Kinetochore recruitment of two nucleolar proteins is required for homolog segregation in meiosis I. Dev Cell 4: 535–548.

45. ChinCF, BennettAM, MaWK, HallMC, YeongFM (2012) Dependence of Chs2 ER export on dephosphorylation by cytoplasmic Cdc14 ensures that septum formation follows mitosis. Mol Biol Cell 23: 45–58.

46. PalaniS, MeitingerF, BoehmME, LehmannWD, PereiraG (2012) Cdc14-dependent dephosphorylation of Inn1 contributes to Inn1-Cyk3 complex formation. J Cell Sci 125: 3091–3096.

47. StegmeierF, HuangJ, RahalR, ZmolikJ, MoazedD, et al. (2004) The replication fork block protein Fob1 functions as a negative regulator of the FEAR network. Curr Biol 14: 467–480.

48. QueraltE, UhlmannF (2008) Separase cooperates with Zds1 and Zds2 to activate Cdc14 phosphatase in early anaphase. J Cell Biol 182: 873–883.

49. TomsonBN, RahalR, ReiserV, Monje-CasasF, MekhailK, et al. (2009) Regulation of Spo12 phosphorylation and its essential role in the FEAR network. Curr Biol 19: 449–460.

50. WaplesWG, ChahwanC, CiechonskaM, LavoieBD (2009) Putting the brake on FEAR: Tof2 promotes the biphasic release of Cdc14 phosphatase during mitotic exit. Mol Biol Cell 20: 245–255.

51. AkiyoshiB, BigginsS (2010) Cdc14-dependent dephosphorylation of a kinetochore protein prior to anaphase in Saccharomyces cerevisiae. Genetics 468: 576–579.

52. HoltLJ, KrutchinskyAN, MorganDO (2008) Positive feedback sharpens the anaphase switch. Nature 454: 353–357.

53. HuhW-K, FalvoJV, GerkeLC, CarrollAS, HowsonRW, et al. (2003) Global analysis of protein localization in budding yeast. Nature 425: 686–691.

54. ShouW, DeshaiesRJ (2002) Multiple telophase arrest bypassed (tab) mutants alleviate the essential requirement for Cdc15 in exit from mitosis in S. cerevisiae. BMC Genet 3: 4.

55. WachA, BrachatA, PöhlmannR, PhilippsenP (1994) New heterologous modules for classical or PCR-based gene disruptions in Saccharomyces cerevisiae. Yeast 10: 1793–1808.

56. KnopM, SiegersK, PereiraG, ZachariaeW, WinsorB, et al. (1999) Epitope tagging of yeast genes using a PCR-based strategy: more tags and improved practical routines. Yeast 15: 963–972.

57. WäschR, CrossFR (2002) APC-dependent proteolysis of the mitotic cyclin Clb2 is essential for mitotic exit. Nature 418: 556–562.

58. EluèreR, OffnerN, VarletI, MotteuxO, SignonL, et al. (2007) Compartmentalization of the functions and regulation of the mitotic cyclin Clb2 in S. cerevisiae. J Cell Sci 120: 702–711.

59. BaillyE, CabantousS, SondazD, BernadacA, SimonMN (2003) Differential cellular localization among mitotic cyclins from Saccharomyces cerevisiae: a new role for the axial budding protein Bud3 in targeting Clb2 to the mother-bud neck. J Cell Sci 116: 4119–4130.

60. LindstromDL, GottschlingDE (2009) The mother enrichment program: a genetic system for facile replicative life span analysis in Saccharomyces cerevisiae. Genetics 183: 413–422.

61. Amberg DC, Burke DJ, Strathern JN (2005) Methods in yeast genetics. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press.

62. UhlmannF, LottspeichF, NasmythK (1999) Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1. Nature 400: 37–42.

63. FoianiM, MariniF, GambaD, LucchiniG, PlevaniP (1994) The B subunit of the DNA polymerase α-primase complex in Saccharomyces cerevisiae executes an essential function at the initial stage of DNA replication. Mol Cell Biol 14: 923–933.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2015 Číslo 1
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#