Down-regulation of Cdk1 activity in G1 coordinates the G1/S gene expression programme with genome replication

  • Natalia García-Blanco
  • Sergio MorenoEmail author


Cell division is regulated by cyclin-dependent kinases (Cdks) and requires the periodic activation and inactivation of transcription factors that generate waves of gene expression in different cell-cycle phases. In fission yeast, the MCB-binding transcription factor (MBF) is activated at the end of G1 and regulates the expression of a set of genes that encode for proteins involved in the G1/S transition and DNA replication. Here, we review the importance of controlling MBF by Cdk activity at the onset of S phase. Furthermore, we emphasize that MBF regulation by Cdk is particularly critical under conditions in which G1 is extended, such as in nitrogen-poor environments, where down-regulation of Cdk activity in G1 is crucial to generate a proper wave of MBF-dependent transcription at the end of G1, which is critical to promote a successful S phase.


Cell cycle G1/S transcription MBF CDK inhibition Rum1 Ste9 Genomic instability dNTPs Nitrogen TORC2 Gad8 



We thank members of the Moreno’s lab for discussions. This work was supported by Grants from the Ministerio de Economía y Competitividad (BFU2017-88335-R) and Junta de Castilla y León (CSI084U16 and CLU-2017-03). NG-B is the recipient of the FPU15/03654 predoctoral training grant from the Ministerio de Educación, Cultura y Deporte.


  1. Aligianni S, Lackner DH, Klier S, Rustici G, Wilhelm BT, Marguerat S, Codlin S, Brazma A, de Bruin RA, Bähler J (2009) The fission yeast homeodomain protein Yox1p binds to MBF and confines MBF-dependent cell-cycle transcription to G1-S via negative feedback. PLoS Genet 5:e1000626CrossRefGoogle Scholar
  2. Attwooll C, Lazzerini Denchi E, Helin K (2004) The E2F family: specific functions and overlapping interests. EMBO J 23:4709–4716CrossRefGoogle Scholar
  3. Aves SJ, Durkacz BW, Carr A, Nurse P (1985) Cloning, sequencing and transcriptional control of the Schizosaccharomyces pombe cdc10 ‘start’ gene. EMBO J 4:457–463CrossRefGoogle Scholar
  4. Ayté J, Leis JF, Herrera A, Tang E, Yang H, DeCaprio JA (1995) The Schizosaccharomyces pombe MBF complex requires heterodimerization for entry into S phase. Mol Cell Biol 15:2589–2599CrossRefGoogle Scholar
  5. Ayté J, Schweitzer C, Zarzov P, Nurse P, DeCaprio JA (2001) Feedback regulation of the MBF transcription factor by cyclin Cig2. Nat Cell Biol 3:1043–1050CrossRefGoogle Scholar
  6. Ayuda-Durán P, Devesa F, Gomes F, Sequeira-Mendes J, Avila-Zarza C, Gómez M, Calzada A (2014) The CDK regulators Cdh1 and Sic1 promote efficient usage of DNA replication origins to prevent chromosomal instability at a chromosome arm. Nucleic Acids Res 42:7057–7068CrossRefGoogle Scholar
  7. Bähler J (2005) Cell-cycle control of gene expression in budding and fission yeast. Annu Rev Genet 39:69–94CrossRefGoogle Scholar
  8. Banyai G, Baïdi F, Coudreuse D, Szilagyi Z (2016) Cdk1 activity acts as a quantitative platform for coordinating cell cycle progression with periodic transcription. Nat Commun 7:11161CrossRefGoogle Scholar
  9. Baum B, Wuarin J, Nurse P (1997) Control of S-phase periodic transcription in the fission yeast mitotic cycle. EMBO J 16:4676–4688CrossRefGoogle Scholar
  10. Benito J, Martín-Castellanos C, Moreno S (1998) Regulation of the G1 phase of the cell cycle by periodic stabilization and degradation of the p25rum1 CDK inhibitor. EMBO J 17:482–497CrossRefGoogle Scholar
  11. Bertoli C, Skotheim JM, de Bruin RA (2013) Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol 14:518–528CrossRefGoogle Scholar
  12. Bester AC, Roniger M, Oren YS, Im MM, Sarni D, Chaoat M, Bensimon A, Zamir G, Shewach DS, Kerem B (2011) Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145:435–446CrossRefGoogle Scholar
  13. Blanco MA, Sánchez-Díaz A, de Prada JM, Moreno S (2000) APC ste9/srw1 promotes degradation of mitotic cyclins in G1 and is inhibited by cdc2 phosphorylation. EMBO J 19:3945–3955CrossRefGoogle Scholar
  14. Breeden LL (2003) Periodic transcription: a cycle within a cycle. Current Biol 13:R31–R38CrossRefGoogle Scholar
  15. Caetano C, Klier S, de Bruin RA (2011) Phosphorylation of the MBF repressor Yox1p by the DNA replication checkpoint keeps the G1/S cell-cycle transcriptional program active. PLoS One 6:e17211CrossRefGoogle Scholar
  16. Caetano C, Limbo O, Farmer S, Klier S, Dovey C, Russell P, de Bruin RA (2014) Tolerance of deregulated G1/S transcription depends on critical G1/S regulon genes to prevent catastrophic genome instability. Cell Rep 9:2279–2289CrossRefGoogle Scholar
  17. Caligiuri M, Beach D (1993) Sct1 functions in partnership with Cdc10 in a transcription complex that activates cell cycle START and inhibits differentiation. Cell 72:607–619CrossRefGoogle Scholar
  18. Carlson CR, Grallert B, Stokke T, Boye E (1999) Regulation of the start of DNA replication in Schizosaccharomyces pombe. J Cell Sci 112:939–946Google Scholar
  19. Chen HZ, Tsai SY, Leone G (2009) Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer 9:785–797CrossRefGoogle Scholar
  20. Chica N, Rozalén AE, Pérez-Hidalgo L, Rubio A, Novak B, Moreno S (2016) Nutritional control of cell size by the Greatwall-Endosulfine-PP2A·B55 pathway. Curr Biol 26:319–330CrossRefGoogle Scholar
  21. Cohen A, Kupiec M, Weisman R (2016) Gad8 protein is found in the nucleus where it interacts with the Mlul cell cycle box-binding factor (MBF) transcriptional complex to regulate the response to DNA replication stress. J Biol Chem 291:9371–9381CrossRefGoogle Scholar
  22. Connolly T, Caligiuri M, Beach D (1997) The Cdc2 protein kinase controls Cdc10/Sct1 complex formation. Mol Biol Cell 8:1105–1115CrossRefGoogle Scholar
  23. Cooper K (2006) Rb, whi it’s not just for metazoans anymore. Oncogene 25:5228–5232CrossRefGoogle Scholar
  24. Correa-Bordes J, Gulli MP, Nurse P (1997) p25rum1 promotes proteolysis of the mitotic B-cyclin p56cdc13 during G1 of the fission yeast cell cycle. EMBO J 16:4657–4664CrossRefGoogle Scholar
  25. Coudreuse D, Nurse P (2010) Driving the cell cycle with a minimal CDK control network. Nature 468:1074–1079CrossRefGoogle Scholar
  26. Cross FR, Buchler NE, Skotheim JM (2011) Evolution of networks and sequences in eukaryotic cell cycle control. Philos Trans R Soc Lond B Biol Sci 366:3532–3544CrossRefGoogle Scholar
  27. Daga RR, Bolaños P, Moreno S (2003) Regulated mRNA stability of the Cdk inhibitor Rum1 links nutrient status to cell cycle progression. Curr Biol 13:2015–2024CrossRefGoogle Scholar
  28. de Bruin RA, Kalashnikova TI, Aslanian A, Wohlschlegel J, Chahwan C, Yates JR, Russell P, Wittenberg C (2008) DNA replication checkpoint promotes G1-S transcription by inactivating the MBF repressor Nrm1. Proc Natl Acad Sci USA 105:11230–11235CrossRefGoogle Scholar
  29. Diffley JF (2004) Regulation of early events in chromosome replication. Curr Biol 14:R778–R7786CrossRefGoogle Scholar
  30. Dimova DK, Dyson NJ (2005) The E2F transcriptional network: old acquaintances with new faces. Oncogene 24:2810–2826CrossRefGoogle Scholar
  31. Fantes P, Nurse P (1977) Control of cell size at division in fission yeast by a growth-modulated size control over nuclear division. Exp Cell Res 107:377–386CrossRefGoogle Scholar
  32. García-Higuera I, Manchado E, Dubus P, Cañamero M, Méndez J, Moreno S, Malumbres M (2008) Genomic stability and tumour suppression by the APC/C cofactor Cdh1. Nat Cell Biol 10:802–811CrossRefGoogle Scholar
  33. Garzón J, Rodríguez R, Kong Z, Chabes A, Rodríguez-Acebes S, Méndez J, Moreno S, García-Higuera I (2017) Shortage of dNTPs underlies altered replication dynamics and DNA breakage in the absence of the APC/C cofactor Cdh1. Oncogene 36:5808–5818CrossRefGoogle Scholar
  34. Gómez-Escoda B, Ivanova T, Calvo IA, Alves-Rodrigues I, Hidalgo E, Ayté J (2011) Yox1 links MBF-dependent transcription to completion of DNA synthesis. EMBO Rep 12:84–89CrossRefGoogle Scholar
  35. Håkansson P, Dahl L, Chilkova O, Domkin V, Thelander L (2006) The Schizosaccharomyces pombe replication inhibitor Spd1 regulates ribonucleotide reductase activity and dNTPs by binding to the large Cdc22 subunit. J Biol Chem 281:1778–1783CrossRefGoogle Scholar
  36. Hendler A, Medina EM, Buchler NE, de Bruin RA, Aharoni A (2018) The evolution of a G1/S transcriptional network in yeasts. Curr Genet 64:81–86CrossRefGoogle Scholar
  37. Ivanova T, Gómez-Escoda B, Hidalgo E, Ayté J (2011) G1/S transcription and the DNA synthesis checkpoint: common regulatory mechanisms. Cell Cycle 10:912–915CrossRefGoogle Scholar
  38. Ivanova T, Alves-Rodrigues I, Gómez-Escoda B, Dutta C, DeCaprio JA, Rhind N, Hidalgo E, Ayté J (2013) The DNA damage and the DNA replication checkpoints converge at the MBF transcription factor. Mol Biol Cell 24:3350–3357CrossRefGoogle Scholar
  39. Kitamura K, Maekawa H, Shimoda C (1998) Fission yeast Ste9, a homolog of Hct1/Cdh1 and Fizzy-related, is a novel negative regulator of cell cycle progression during G1-phase. Mol Biol Cell 9:1065–1080CrossRefGoogle Scholar
  40. Kominami K, Seth-Smith H, Toda T (1998) Apc10 and Ste9/Srw1, two regulators of the APC-cyclosome, as well as the CDK inhibitor Rum1 are required for G1 cell-cycle arrest in fission yeast. EMBO J 17:5388–5399CrossRefGoogle Scholar
  41. Lengronne A, Schwob E (2002) The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G1. Mol Cell 9:1067–1078CrossRefGoogle Scholar
  42. Liu C, Powell KA, Mundt K, Wu L, Carr AM, Caspari T (2003) Cop9/signalosome subunits and Pcu4 regulate ribonucleotide reductase by both checkpoint-dependent and -independent mechanisms. Genes Dev 17:1130–1140CrossRefGoogle Scholar
  43. Marguerat S, Jensen TS, de Lichtenberg U, Wilhelm BT, Jensen LJ, Bähler J (2006) The more the merrier: comparative analysis of microarray studies on cell cycle-regulated genes in fission yeast. Yeast 23:261–277CrossRefGoogle Scholar
  44. Martín R, López-Avilés S (2018) Express yourself: how PP2A-B55Pab1 helps TORC1 talk to TORC2. Curr Genet 64:43–51CrossRefGoogle Scholar
  45. Martín R, Portantier M, Chica N, Nyquist-Andersen M, Mata J, López-Avilés S (2017) A PP2A-B55-mediated crosstalk between TORC1 and TORC2 regulates the differentiation response in fission yeast. Curr Biol 27:175–188CrossRefGoogle Scholar
  46. Martín-Castellanos C, Blanco MA, de Prada JM, Moreno S (2000) The puc1 cyclin regulates the G1 phase of the fission yeast cell cycle in response to cell size. Mol Biol Cell 11:543–554CrossRefGoogle Scholar
  47. Miyamoto M, Tanaka K, Okayama H (1994) res2+, a new member of the cdc10+/SWI4 family, controls the ‘start’ of mitotic and meiotic cycles in fission yeast. EMBO J 13:1873–1880CrossRefGoogle Scholar
  48. Moreno S, Nurse P (1994) Regulation of progression through the G1 phase of the cell cycle by the rum1 gene. Nature 367:236–242CrossRefGoogle Scholar
  49. Nakashima N, Tanaka K, Sturm S, Okayama H (1995) Fission yeast Rep2 is a putative transcriptional activator subunit for the cell cycle “start” function of Res2-Cdc10. EMBO J 14:4794–4802CrossRefGoogle Scholar
  50. Nurse P (1990) Universal control mechanism regulating onset of M-phase. Nature 344:503–508CrossRefGoogle Scholar
  51. Oliva A, Rosebrock A, Ferrezuelo F, Pyne S, Chen H, Skiena S, Futcher B, Leatherwood J (2005) The cell cycle-regulated genes of Schizosaccharomyces pombe. PloS Biol 3:e225CrossRefGoogle Scholar
  52. Pai CC, Kishkevich A, Deegan RS, Keszthelyi A, Folkes L, Kearsey SE, De León N, Soriano I, de Bruin RAM, Carr AM et al (2017) Set2 methyltransferase facilitates DNA replication and promotes genotoxic stress responses through MBF-dependent transcription. Cell Rep 2:2693–2705CrossRefGoogle Scholar
  53. Peng X, Karuturi RK, Miller LD, Lin K, Jia Y, Kondu P, Wang L, Wong LS, Liu ET, Balasubramanian MK et al (2005) Identification of cell cycle-regulated genes in fission yeast. Mol Biol Cell 16:1026–1042CrossRefGoogle Scholar
  54. Pérez-Hidalgo L, Moreno S (2016) Nutrients control cell size. Cell Cycle 15:1655–1656CrossRefGoogle Scholar
  55. Pérez-Hidalgo L, Moreno S (2017) Coupling TOR to the cell cycle by the Greatwall–Endosulfine–PP2A-B55 pathway. Biomolecules 7:59CrossRefGoogle Scholar
  56. Petersen J, Nurse P (2007) TOR signalling regulates mitotic commitment through the stress MAP kinase pathway and the Polo and Cdc2 kinases. Nat Cell Biol 9:1263–1272CrossRefGoogle Scholar
  57. Purtill FS, Whitehall SK, Williams ES, McInerny CJ, Sharrocks AD, Morgan BA (2011) A homeodomain transcription factor regulates the DNA replication checkpoint in yeast. Cell Cycle 10:664–670CrossRefGoogle Scholar
  58. Reymond A, Marks J, Simanis V (1993) The activity of S pombe DSC-1 -like factor is cell cycle regulated and dependent on the activity of p34cdc2. EMBO J 12:4325–4334CrossRefGoogle Scholar
  59. Rubio A, García-Blanco N, Vázquez-Bolado A, Belén Suárez M, Moreno S (2018) Nutritional cell cycle reprogramming reveals that inhibition of Cdk1 is required for proper MBF-dependent transcription. J Cell Sci 131:jcs218743CrossRefGoogle Scholar
  60. Rustici G, Mata J, Kivinen K, Lió P, Penkett CJ, Burns G, Hayles J, Brazma A, Nurse P, Bähler J (2004) Periodic gene expression program of the fission yeast cell cycle. Nat Genet 36:809–817CrossRefGoogle Scholar
  61. Stern B, Nurse P (1998) Cyclin B proteolysis and the cyclin-dependent kinase inhibitor Rum1p are required for pheromone-induced G1 arrest in fission yeast. Mol Biol Cell 9:1309–1321CrossRefGoogle Scholar
  62. Sveiczer A, Horváth A (2017) How do fission yeast cells grow and connect growth to the mitotic cycle? Curr Genet 63:165–173CrossRefGoogle Scholar
  63. Tahara S, Tanak K, Yuasa Y, Okayama H (1998) Functional domains of Rep2, a transcriptional activator subunit for Res2-Cdc10, controlling the cell cycle “start”. Mol Biol Cell 9:1577–1588CrossRefGoogle Scholar
  64. Tanaka S, Diffley JF (2002) Deregulated G1-cyclin expression induces genomic instability by preventing efficient pre-RC formation. Genes Dev 16:2639–2649CrossRefGoogle Scholar
  65. Tanaka K, Okazaki K, Okazaki N, Ueda T, Sugiyama A, Nojima H, Okayama H (1992) A new cdc gene required for S phase entry of Schizosaccharomyces pombe encodes a protein similar to the cdc10 + and SWI4 gene products. EMBO J 11:4923–4932CrossRefGoogle Scholar
  66. Trimarchi JM, Fairchild B, Verona R, Moberg K, Andon N, Lees JA (1998) E2F-6, a member of the E2F family that can behave as a transcriptional repressor. Proc Natl Acad Sci USA 95:2850–2855CrossRefGoogle Scholar
  67. Whitehall S, Stacey P, Dawson K, Jones N (1999) Cell cycle-regulated transcription in fission yeast: Cdc10-Res protein interactions during the cell cycle and domains required for regulated transcription. Mol Biol Cell 10:3705–3715CrossRefGoogle Scholar
  68. Wittenberg C, Reed SI (2005) Cell cycle-dependent transcription in yeast: promoters, transcription factors, and transcriptomes. Oncogene 24:2746–2755CrossRefGoogle Scholar
  69. Wuarin J, Buck V, Nurse P, Millar JBA (2002) Stable association of mitotic cyclin B/Cdc2 to replication origins prevents endoreduplication. Cell 111:419–431CrossRefGoogle Scholar
  70. Yamaguchi S, Murakami H, Okayama H (1997) A WD repeat protein controls the cell cycle and differentiation by negatively regulating Cdc2/B-type cyclin complexes. Mol Biol Cell 8:2475–2486CrossRefGoogle Scholar
  71. Yamaguchi S, Okayama H, Nurse P (2000) Fission yeast Fizzy-related protein srw1p is a G1- Specific promoter of mitotic cyclin B degradation. EMBO J 19:3945–3955CrossRefGoogle Scholar
  72. Yamano H, Kitamura K, Kominami K, Lehmann A, Katayama S, Hunt T, Toda T (2000) The spike of S phase cyclin Cig2 expression at the G1-S border in fission yeast requires both APC and SCF ubiquitin ligases. Mol Cell 6:1377–1387CrossRefGoogle Scholar
  73. Zhu Y, Takeda T, Whitehall S, Peat N, Jones N (1997) Functional characterization of the fission yeast Start-specific transcription factor Res2. EMBO J 16:1023–1034CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Functional Biology and GenomicsCSIC, University of SalamancaSalamancaSpain

Personalised recommendations