Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response

Nature Reviews Molecular Cell Biology volume 14, pages 563–580 (2013)Cite this article

Subjects

Key Points

  • Coordinated cell cycle progression is a complex challenge for eukaryotic cells. In response to DNA damage, a plethora of molecular signals must be integrated to establish cell cycle checkpoints, allowing time for DNA repair.

  • Phospho-Ser/Thr-binding domains act as central regulators (hubs) that integrate the activity of multiple kinase signalling cascades to coordinate cell cycle progression and checkpoint control following genotoxic stress.

  • Phospho-Ser/Thr-binding domains, such as 14-3-3 proteins, WW domains, Polo-box domains, WD40 repeats, BRCA1 carboxy-terminal (BRCT) domains and forkhead-associated (FHA) domains can be found in numerous proteins involved in cell cycle regulation and the DNA damage response and are conserved from metazoans to the simplest single cell eukaryotes.

  • 14-3-3 proteins control mitotic progression and the G2–M checkpoint by regulating the subcellular localization and the catalytic activity of their phosphorylated client proteins.

  • The WW domain-containing protein PIN1 slows progression through mitosis and is also required for mitotic exit and the intra-S phase checkpoint.

  • Polo-box domains are a hallmark feature of Polo-like kinases (PLKs) and help localize PLKs to their substrates and regulate the activity of their kinase domains. PLK1 activity is required for the timely activation of CDC25B and CDC25C to initiate mitosis, for the coordinated progression of cells through mitosis and for inactivating DNA damage checkpoints once repair is complete.

  • WD40 domains can be found in a subset of F-box proteins, including βTrCP (β-transducin repeat-containing protein), CDC4 and FBW7.

  • SCFβTrCP (SKP1–cullin 1–F-box complex containing βTrCP)-dependent substrate degradation controls two opposing cellular responses following genotoxic stress: checkpoint-activating degradation of CDC25A following DNA damage and checkpoint-inactivating claspin and WEE1 degradation following damage repair.

  • BRCT domains are present in various DNA replication and repair proteins, including BRCA1, MDC1 (mediator of DNA damage checkpoint protein 1), 53BP1 (p53 binding protein 1), TOPBP1 (topoisomerase-binding protein 1), PTIP (PAX-interacting protein 1), XRCC1 (X-ray repair cross-complementing 1) and DNA ligase IV. BRCT domain-containing proteins control numerous diverse processes, including homologous recombination-mediated DNA double strand repair and base excision repair, as well as cell cycle checkpoint activation and maintenance.

  • FHA domains are found in proteins involved in transcription, DNA damage repair and cell cycle control, as well as in kinesin-like motors and regulators of small G proteins. Within the DNA damage response cascade, FHA domain-containing proteins, such as RING finger 8 (RNF8) and MDC1 control the assembly of signalling complexes at the site of the DNA lesion, whereas the FHA domain-containing checkpoint kinase CHK2 acts as a mobile messenger within the nucleoplasm.

Abstract

Coordinated progression through the cell cycle is a complex challenge for eukaryotic cells. Following genotoxic stress, diverse molecular signals must be integrated to establish checkpoints specific for each cell cycle stage, allowing time for various types of DNA repair. Phospho-Ser/Thr-binding domains have emerged as crucial regulators of cell cycle progression and DNA damage signalling. Such domains include 14-3-3 proteins, WW domains, Polo-box domains (in PLK1), WD40 repeats (including those in the E3 ligase SCFβTrCP), BRCT domains (including those in BRCA1) and FHA domains (such as in CHK2 and MDC1). Progress has been made in our understanding of the motif (or motifs) that these phospho-Ser/Thr-binding domains connect with on their targets and how these interactions influence the cell cycle and DNA damage response.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Phospho-Ser/Thr-binding domains in cell cycle progression and checkpoint signalling.
Figure 2: 14-3-3 and WW domains control the activity and subcellular localization of client proteins.
Figure 3: Polo-box and WD40 domains control cell cycle progression and restart after DNA damage.
Figure 4: Tandem BRCT (BRCT)2 and FHA domains mediate cell cycle control in response to DNA damage.
Figure 5: FHA and (BRCT)2 domain interactions in the DNA damage response.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Pawson, T. & Nash, P. Protein–protein interactions define specificity in signal transduction. Genes Dev. 14, 1027–1047 (2000).

    CAS  PubMed  Google Scholar 

  2. Pawson, T. & Nash, P. Assembly of cell regulatory systems through protein interaction domains. Science 300, 445–452 (2003).

    CAS  PubMed  Google Scholar 

  3. Matsuda, M., Mayer, B. J., Fukui, Y. & Hanafusa, H. Binding of transforming protein, 47gag-crk, to a broad range of phosphotyrosine-containing proteins. Science 248, 1537–1539 (1990).

    CAS  PubMed  Google Scholar 

  4. Feng, G. S., Hui, C. C. & Pawson, T. SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science 259, 1607–1611 (1993).

    CAS  PubMed  Google Scholar 

  5. Songyang, Z. et al. SH2 domains recognize specific phosphopeptide sequences. Cell 72, 767–778 (1993).

    CAS  PubMed  Google Scholar 

  6. Waksman, G., Shoelson, S. E., Pant, N., Cowburn, D. & Kuriyan, J. Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: crystal structures of the complexed and peptide-free forms. Cell 72, 779–790 (1993).

    CAS  PubMed  Google Scholar 

  7. Cohen, P., Antoniw, J. F., Nimmo, H. G. & Yeaman, S. J. Protein phosphorylation and hormone action. Ciba Found. Symp. 41, 281–295 (1976).

    CAS  PubMed  Google Scholar 

  8. Larner, J. et al. Hormonal control of glycogen metabolism. Adv. Exp. Med. Biol. 111, 103–123 (1979).

    CAS  PubMed  Google Scholar 

  9. Rubin, C. S. & Rosen, O. M. Protein phosphorylation. Annu. Rev. Biochem. 44, 831–887 (1975).

    CAS  PubMed  Google Scholar 

  10. Reinhardt, H. C. & Yaffe, M. B. Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2. Curr. Opin. Cell Biol. 21, 245–255 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Frontini, M. et al. The CDK subunit CKS2 counteracts CKS1 to control cyclin A/CDK2 activity in maintaining replicative fidelity and neurodevelopment. Dev. Cell 23, 356–370 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Ma, H. T. & Poon, R. Y. How protein kinases co-ordinate mitosis in animal cells. Biochem. J. 435, 17–31 (2011).

    CAS  PubMed  Google Scholar 

  13. Besson, A., Dowdy, S. F. & Roberts, J. M. CDK inhibitors: cell cycle regulators and beyond. Dev. Cell 14, 159–169 (2008).

    CAS  PubMed  Google Scholar 

  14. Donzelli, M. & Draetta, G. F. Regulating mammalian checkpoints through Cdc25 inactivation. EMBO Rep. 4, 671–677 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Furukawa, Y. et al. Demonstration of the phosphorylation-dependent interaction of tryptophan hydroxylase with the 14-3-3 protein. Biochem. Biophys. Res. Commun. 194, 144–149 (1993).

    CAS  PubMed  Google Scholar 

  16. Fantl, W. J. et al. Activation of Raf-1 by 14-3-3 proteins. Nature 371, 612–614 (1994).

    CAS  PubMed  Google Scholar 

  17. Freed, E., Symons, M., Macdonald, S. G., McCormick, F. & Ruggieri, R. Binding of 14-3-3 proteins to the protein kinase Raf and effects on its activation. Science 265, 1713–1716 (1994).

    CAS  PubMed  Google Scholar 

  18. Fu, H. et al. Interaction of the protein kinase Raf-1 with 14-3-3 proteins. Science 266, 126–129 (1994). Describes, together with references 16 and 17, for the first time a requirement for 14-3-3 binding in RAF activation.

    CAS  PubMed  Google Scholar 

  19. Broadbelt, K. G. et al. Brainstem deficiency of the 14-3-3 regulator of serotonin synthesis: a proteomics analysis in the sudden infant death syndrome. Mol. Cell Proteomics 11, M111.009530 (2012).

    PubMed  Google Scholar 

  20. Morrison, D. K. The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development. Trends Cell Biol. 19, 16–23 (2009).

    CAS  PubMed  Google Scholar 

  21. Muslin, A. J., Tanner, J. W., Allen, P. M. & Shaw, A. S. Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell 84, 889–897 (1996). A landmark paper that, using phospho- and non-phosphopeptides from RAF, discovers that 14-3-3 is a phospho-Ser/Thr-binding protein. This is the first description of a phospho-Ser/Thr-specific binding protein.

    CAS  PubMed  Google Scholar 

  22. Yaffe, M. B. et al. The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91, 961–971 (1997). Identifies, using phospho-Ser-oriented peptide libraries, two 14-3-3 phospho-binding motifs. The X-ray crystal structure of a 14-3-3–phosphopeptide (from polyoma middle T antigen) complex is also solved, providing a structural basis for phospho-specific binding.

    CAS  PubMed  Google Scholar 

  23. Rittinger, K. et al. Structural analysis of 14-3-3 phosphopeptide complexes identifies a dual role for the nuclear export signal of 14-3-3 in ligand binding. Mol. Cell 4, 153–166 (1999).

    CAS  PubMed  Google Scholar 

  24. Coblitz, B. et al. C-terminal recognition by 14-3-3 proteins for surface expression of membrane receptors. J. Biol. Chem. 280, 36263–36272 (2005).

    CAS  PubMed  Google Scholar 

  25. Aitken, A. Functional specificity in 14-3-3 isoform interactions through dimer formation and phosphorylation. Chromosome location of mammalian isoforms and variants. Plant Mol. Biol. 50, 993–1010 (2002).

    CAS  PubMed  Google Scholar 

  26. Wilker, E. W., Grant, R. A., Artim, S. C. & Yaffe, M. B. A structural basis for 14-3-3σ functional specificity. J. Biol. Chem. 280, 18891–18898 (2005).

    CAS  PubMed  Google Scholar 

  27. Benzinger, A. et al. Targeted proteomic analysis of 14-3-3σ, a p53 effector commonly silenced in cancer. Mol. Cell Proteom. 4, 785–795 (2005).

    CAS  Google Scholar 

  28. Sluchanko, N. N. & Gusev, N. B. Oligomeric structure of 14-3-3 protein: what do we know about monomers? FEBS Lett. 586, 4249–4256 (2012).

    CAS  PubMed  Google Scholar 

  29. Gardino, A. K., Smerdon, S. J. & Yaffe, M. B. Structural determinants of 14-3-3 binding specificities and regulation of subcellular localization of 14-3-3–ligand complexes: a comparison of the X-ray crystal structures of all human 14-3-3 isoforms. Semin. Cancer Biol. 16, 173–182 (2006).

    CAS  PubMed  Google Scholar 

  30. Xiao, B. et al. Structure of a 14-3-3 protein and implications for coordination of multiple signalling pathways. Nature 376, 188–191 (1995).

    CAS  PubMed  Google Scholar 

  31. Liu, D. et al. Crystal structure of the ζ-isoform of the 14-3-3 protein. Nature 376, 191–194 (1995).

    CAS  PubMed  Google Scholar 

  32. Van Der Hoeven, P. C., Van Der Wal, J. C., Ruurs, P., Van Dijk, M. C. & Van Blitterswijk, J. 14-3-3 isotypes facilitate coupling of protein kinase C-ζ to Raf-1: negative regulation by 14-3-3 phosphorylation. Biochem. J. 345, 297–306 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zha, J., Harada, H., Yang, E., Jockel, J. & Korsmeyer, S. J. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-XL . Cell 87, 619–628 (1996).

    CAS  PubMed  Google Scholar 

  34. Brunet, A. et al. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J. Cell Biol. 156, 817–828 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Yaffe, M. B. How do 14-3-3 proteins work? Gatekeeper phosphorylation and the molecular anvil hypothesis. FEBS Lett. 513, 53–57 (2002).

    CAS  PubMed  Google Scholar 

  36. Tinti, M., Johnson, C., Toth, R., Ferrier, D. E. & Mackintosh, C. Evolution of signal multiplexing by 14-3-3-binding 2R-ohnologue protein families in the vertebrates. Open Biol. 2, 120103 (2012).

    PubMed  PubMed Central  Google Scholar 

  37. Obsil, T., Ghirlando, R., Klein, D. C., Ganguly, S. & Dyda, F. Crystal structure of the 14-3-3ζ:serotonin N-acetyltransferase complex: a role for scaffolding in enzyme regulation. Cell 105, 257–267 (2001).

    CAS  PubMed  Google Scholar 

  38. Yoshida, K., Yamaguchi, T., Natsume, T., Kufe, D. & Miki, Y. JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nature Cell Biol. 7, 278–285 (2005).

    CAS  PubMed  Google Scholar 

  39. Williams, D. M. et al. NMR spectroscopy of 14-3-3ζ reveals a flexible C-terminal extension: differentiation of the chaperone and phosphoserine-binding activities of 14-3-3ζ. Biochem. J. 437, 493–503 (2011).

    CAS  PubMed  Google Scholar 

  40. Aitken, A. et al. Post-translationally modified 14-3-3 isoforms and inhibition of protein kinase C. Mol. Cell Biochem. 149–150, 41–49 (1995).

    PubMed  Google Scholar 

  41. Dubois, T. et al. 14-3-3 is phosphorylated by casein kinase I on residue 233. Phosphorylation at this site in vivo regulates Raf/14-3-3 interaction. J. Biol. Chem. 272, 28882–28888 (1997).

    CAS  PubMed  Google Scholar 

  42. Megidish, T., Cooper, J., Zhang, L., Fu, H. & Hakomori, S. A novel sphingosine-dependent protein kinase (SDK1) specifically phosphorylates certain isoforms of 14-3-3 protein. J. Biol. Chem. 273, 21834–21845 (1998).

    CAS  PubMed  Google Scholar 

  43. Powell, D. W. et al. Proteomic identification of 14-3-3ζ as a mitogen-activated protein kinase-activated protein kinase 2 substrate: role in dimer formation and ligand binding. Mol. Cell. Biol. 23, 5376–5387 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Sunayama, J., Tsuruta, F., Masuyama, N. & Gotoh, Y. JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3. J. Cell Biol. 170, 295–304 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Tsuruta, F. et al. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J. 23, 1889–1899 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lalle, M., Salzano, A. M., Crescenzi, M. & Pozio, E. The Giardia duodenalis 14-3-3 protein is post-translationally modified by phosphorylation and polyglycylation of the C-terminal tail. J. Biol. Chem. 281, 5137–5148 (2006).

    CAS  PubMed  Google Scholar 

  47. Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009).

    CAS  PubMed  Google Scholar 

  48. Pines, J. Four-dimensional control of the cell cycle. Nature Cell Biol. 1, E73–E79 (1999).

    CAS  PubMed  Google Scholar 

  49. Boutros, R., Lobjois, V. & Ducommun, B. CDC25 phosphatases in cancer cells: key players? Good targets? Nature Rev. Cancer 7, 495–507 (2007).

    CAS  Google Scholar 

  50. Karlsson, C., Katich, S., Hagting, A., Hoffmann, I. & Pines, J. Cdc25B and Cdc25C differ markedly in their properties as initiators of mitosis. J. Cell Biol. 146, 573–584 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Gabrielli, B. G. et al. Cytoplasmic accumulation of cdc25B phosphatase in mitosis triggers centrosomal microtubule nucleation in HeLa cells. J. Cell Sci. 109, 1081–1093 (1996).

    CAS  PubMed  Google Scholar 

  52. Nishijima, H., Nishitani, H., Seki, T. & Nishimoto, T. A dual-specificity phosphatase Cdc25B is an unstable protein and triggers p34cdc2/cyclin B activation in hamster BHK21 cells arrested with hydroxyurea. J. Cell Biol. 138, 1105–1116 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Toyoshima-Morimoto, F., Taniguchi, E. & Nishida, E. Plk1 promotes nuclear translocation of human Cdc25C during prophase. EMBO Rep. 3, 341–348 (2002). Shows that PLK1 directly phosphorylates CDC25C in HeLa cells within a nuclear export signal to drive CDC25C nuclear accumulation and mitotic progression.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang, R. et al. Regulation of Cdc25C by ERK-MAP kinases during the G2/M transition. Cell 128, 1119–1132 (2007).

    CAS  PubMed  Google Scholar 

  55. Hoffmann, I., Clarke, P. R., Marcote, M. J., Karsenti, E. & Draetta, G. Phosphorylation and activation of human cdc25-C by cdc2–cyclin B and its involvement in the self-amplification of MPF at mitosis. EMBO J. 12, 53–63 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Izumi, T. & Maller, J. L. Elimination of cdc2 phosphorylation sites in the cdc25 phosphatase blocks initiation of M-phase. Mol. Biol. Cell 4, 1337–1350 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Elia, A. E., Cantley, L. C. & Yaffe, M. B. Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates. Science 299, 1228–1231 (2003). The first identification of the PBD of PLKs as a phospho-Ser/Thr-binding module that targets PLK1 to its substrates following a priming phosphorylation by CDKs or other kinases.

    CAS  PubMed  Google Scholar 

  58. Kumagai, A., Yakowec, P. S. & Dunphy, W. G. 14-3-3 proteins act as negative regulators of the mitotic inducer Cdc25 in Xenopus egg extracts. Mol. Biol. Cell 9, 345–354 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Graves, P. R., Lovly, C. M., Uy, G. L. & Piwnica-Worms, H. Localization of human Cdc25C is regulated both by nuclear export and 14-3-3 protein binding. Oncogene 20, 1839–1851 (2001).

    CAS  PubMed  Google Scholar 

  60. Kumagai, A. & Dunphy, W. G. Binding of 14-3-3 proteins and nuclear export control the intracellular localization of the mitotic inducer Cdc25. Genes Dev. 13, 1067–1072 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Davezac, N. et al. Regulation of CDC25B phosphatases subcellular localization. Oncogene 19, 2179–2185 (2000).

    CAS  PubMed  Google Scholar 

  62. Forrest, A. & Gabrielli, B. Cdc25B activity is regulated by 14-3-3. Oncogene 20, 4393–4401 (2001).

    CAS  PubMed  Google Scholar 

  63. Bartek, J., Lukas, C. & Lukas, J. Checking on DNA damage in S phase. Nature Rev. Mol. Cell Biol. 5, 792–804 (2004).

    CAS  Google Scholar 

  64. Margolis, S. S. et al. PP1 control of M phase entry exerted through 14-3-3-regulated Cdc25 dephosphorylation. EMBO J. 22, 5734–5745 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Astuti, P., Boutros, R., Ducommun, B. & Gabrielli, B. Mitotic phosphorylation of Cdc25B Ser321 disrupts 14-3-3 binding to the high affinity Ser323 site. J. Biol. Chem. 285, 34364–34370 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Bulavin, D. V. et al. Dual phosphorylation controls Cdc25 phosphatases and mitotic entry. Nature Cell Biol. 5, 545–551 (2003). Shows that phosphorylation of CDC25C on Ser214 by CDK1 prevents its subsequent phosphorylation on Ser216 during mitosis; this prevents 14-3-3 binding. Suggests that this creates a positive feedback loop during mitosis that prevents CDC25C inactivation and contributes to the rapid 'all-or-none' activation of CDK1.

    CAS  PubMed  Google Scholar 

  67. Margolis, S. S. et al. Role for the PP2A/B56dδ phosphatase in regulating 14-3-3 release from Cdc25 to control mitosis. Cell 127, 759–773 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Macurek, L. et al. Polo-like kinase-1 is activated by Aurora A to promote checkpoint recovery. Nature 455, 119–123 (2008). Establishes a role for the complex of Aurora A and its co-activator Bora in release of the G2–M checkpoint through direct phosphorylation and activation of PLK1 on Thr210.

    CAS  PubMed  Google Scholar 

  69. Seki, A., Coppinger, J. A., Jang, C. Y., Yates, J. R. & Fang, G. Bora and the kinase Aurora A cooperatively activate the kinase Plk1 and control mitotic entry. Science 320, 1655–1658 (2008). Shows that accumulation of Bora during G2 results in Bora–PLK1 binding that overcomes autoinhibition of PLK1 by the PBD. Bora also faciliated Aurora A-dependent phosphorylation and activation of PLK1 on Thr210 in undamaged HeLa cells to promote both G2–M transition and the phosphorylation-induced destruction of Bora in mitosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Yoo, H. Y., Kumagai, A., Shevchenko, A. & Dunphy, W. G. Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase. Cell 117, 575–588 (2004). Shows, using X. laevis egg extracts, that the CHK1 activator protein claspin becomes phosphorylated during a replication-induced checkpoint block, creating a binding site for PLX1. During adaptation to prolonged checkpoint arrest, PLX1 binding and phosphorylation of claspin, release of claspin from chromatin and inactivation of the checkpoint kinase CHK1 allow cells to progress through the cell cycle.

    CAS  PubMed  Google Scholar 

  71. Mamely, I. et al. Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery. Curr. Biol. 16, 1950–1955 (2006).

    CAS  PubMed  Google Scholar 

  72. Peschiaroli, A. et al. SCFβTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response. Mol. Cell 23, 319–329 (2006).

    CAS  PubMed  Google Scholar 

  73. Giunta, S., Belotserkovskaya, R. & Jackson, S. P. DNA damage signaling in response to double-strand breaks during mitosis. J. Cell Biol. 190, 197–207 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. van Vugt, M. A. et al. A mitotic phosphorylation feedback network connects Cdk1, Plk1, 53BP1, and Chk2 to inactivate the G2/M DNA damage checkpoint. PLoS Biol. 8, e1000287 (2010).

    PubMed  PubMed Central  Google Scholar 

  75. Wilker, E. W. et al. 14-3-3σ controls mitotic translation to facilitate cytokinesis. Nature 446, 329–332 (2007).

    CAS  PubMed  Google Scholar 

  76. Cornelis, S. et al. Identification and characterization of a novel cell cycle-regulated internal ribosome entry site. Mol. Cell 5, 597–605 (2000).

    CAS  PubMed  Google Scholar 

  77. Hu, D., Valentine, M., Kidd, V. J. & Lahti, J. M. CDK11p58 is required for the maintenance of sister chromatid cohesion. J. Cell Sci. 120, 2424–2434 (2007).

    CAS  PubMed  Google Scholar 

  78. Petretti, C. et al. The PITSLRE/CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation. EMBO Rep. 7, 418–424 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Saurin, A. T. et al. The regulated assembly of a PKCε complex controls the completion of cytokinesis. Nature Cell Biol. 10, 891–901 (2008).

    CAS  PubMed  Google Scholar 

  80. Douglas, M. E., Davies, T., Joseph, N. & Mishima, M. Aurora B and 14-3-3 coordinately regulate clustering of centralspindlin during cytokinesis. 20, 927–933 Curr. Biol. (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Mishima, M., Kaitna, S. & Glotzer, M. Central spindle assembly and cytokinesis require a kinesin-like protein/RhoGAP complex with microtubule bundling activity. Dev. Cell 2, 41–54 (2002).

    CAS  PubMed  Google Scholar 

  82. Yuce, O., Piekny, A. & Glotzer, M. An ECT2–centralspindlin complex regulates the localization and function of RhoA. J. Cell Biol. 170, 571–582 (2005).

    PubMed  PubMed Central  Google Scholar 

  83. Bork, P. & Sudol, M. The WW domain: a signalling site in dystrophin? Trends Biochem. Sci. 19, 531–533 (1994).

    CAS  PubMed  Google Scholar 

  84. Macias, M. J., Gervais, V., Civera, C. & Oschkinat, H. Structural analysis of WW domains and design of a WW prototype. Nature Struct. Biol. 7, 375–379 (2000).

    CAS  PubMed  Google Scholar 

  85. Aasland, R. et al. Normalization of nomenclature for peptide motifs as ligands of modular protein domains. FEBS Lett. 513, 141–144 (2002).

    CAS  PubMed  Google Scholar 

  86. Otte, L. et al. WW domain sequence activity relationships identified using ligand recognition propensities of 42 WW domains. Protein Sci. 12, 491–500 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Lu, K. P., Hanes, S. D. & Hunter, T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380, 544–547 (1996).

    CAS  PubMed  Google Scholar 

  88. Winkler, K. E., Swenson, K. I., Kornbluth, S. & Means, A. R. Requirement of the prolyl isomerase Pin1 for the replication checkpoint. Science 287, 1644–1647 (2000).

    CAS  PubMed  Google Scholar 

  89. Yaffe, M. B. et al. Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science 278, 1957–1960 (1997).

    CAS  PubMed  Google Scholar 

  90. Crenshaw, D. G., Yang, J., Means, A. R. & Kornbluth, S. The mitotic peptidyl-prolyl isomerase, Pin1, interacts with Cdc25 and Plx1. EMBO J. 17, 1315–1327 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Shen, M., Stukenberg, P. T., Kirschner, M. W. & Lu, K. P. The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Genes Dev. 12, 706–720 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kamimoto, T., Zama, T., Aoki, R., Muro, Y. & Hagiwara, M. Identification of a novel kinesin-related protein, KRMP1, as a target for mitotic peptidyl-prolyl isomerase Pin1. J. Biol. Chem. 276, 37520–37528 (2001).

    CAS  PubMed  Google Scholar 

  93. Lu, P. J., Zhou, X. Z., Shen, M. & Lu, K. P. Function of WW domains as phosphoserine- or phosphothreonine-binding modules. Science 283, 1325–1328 (1999). The first description of WW domain binding to phospho-Ser/Thr-containing peptides, as well as a demonstration that the WW domain of PIN1 interacts with mutliple mitotic phosphoproteins, including CDC25C.

    CAS  PubMed  Google Scholar 

  94. Verdecia, M. A., Bowman, M. E., Lu, K. P., Hunter, T. & Noel, J. P. Structural basis for phosphoserine–proline recognition by group IV WW domains. Nature Struct. Biol. 7, 639–643 (2000). Establishes the structural basis for phosphopeptide binding by PIN1 and PIN1-like WW domains.

    CAS  PubMed  Google Scholar 

  95. Patra, D., Wang, S. X., Kumagai, A. & Dunphy, W. G. The Xenopus Suc1/Cks protein promotes the phosphorylation of G2/M regulators. J. Biol. Chem. 274, 36839–36842 (1999).

    CAS  PubMed  Google Scholar 

  96. Landrieu, I. et al. p13SUC1 and the WW domain of PIN1 bind to the same phosphothreonine–proline epitope. J. Biol. Chem. 276, 1434–1438 (2001).

    CAS  PubMed  Google Scholar 

  97. Stukenberg, P. T. & Kirschner, M. W. Pin1 acts catalytically to promote a conformational change in Cdc25. Mol. Cell 7, 1071–1083 (2001). Shows that sub-stoichiometric amounts of PIN1 in X. laevis extracts bind to and isomerize the CDK1-phosphorylated form of CDC25. This PIN1 binding and conformational change slightly inhibits CDC25 phosphatase activity, but markedly enhances CDC25 activity if PLK1 is present, presumably enhancing mitotic progression in vivo.

    CAS  PubMed  Google Scholar 

  98. Zhou, X. Z. et al. Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and Tau proteins. Mol. Cell 6, 873–883 (2000).

    CAS  PubMed  Google Scholar 

  99. Okamoto, K. & Sagata, N. Mechanism for inactivation of the mitotic inhibitory kinase Wee1 at M phase. Proc. Natl Acad. Sci. USA 104, 3753–3758 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Bernis, C. et al. Pin1 stabilizes Emi1 during G2 phase by preventing its association with SCFβtrcp. EMBO Rep. 8, 91–98 (2007).

    CAS  PubMed  Google Scholar 

  101. Archambault, V. & Glover, D. M. Polo-like kinases: conservation and divergence in their functions and regulation. Nature Rev. Mol. Cell Biol. 10, 265–275 (2009).

    CAS  Google Scholar 

  102. Lindqvist, A., Rodriguez-Bravo, V. & Medema, R. H. The decision to enter mitosis: feedback and redundancy in the mitotic entry network. J. Cell Biol. 185, 193–202 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Golsteyn, R. M. et al. Cell cycle analysis and chromosomal localization of human Plk1, a putative homologue of the mitotic kinases Drosophila polo and Saccharomyces cerevisiae Cdc5. J. Cell Sci. 107, 1509–1517 (1994).

    CAS  PubMed  Google Scholar 

  104. Jang, Y. J., Ma, S., Terada, Y. & Erikson, R. L. Phosphorylation of threonine 210 and the role of serine 137 in the regulation of mammalian polo-like kinase. J. Biol. Chem. 277, 44115–44120 (2002).

    CAS  PubMed  Google Scholar 

  105. Kelm, O., Wind, M., Lehmann, W. D. & Nigg, E. A. Cell cycle-regulated phosphorylation of the Xenopus polo-like kinase Plx1. J. Biol. Chem. 277, 25247–25256 (2002).

    CAS  PubMed  Google Scholar 

  106. Johnson, T. M., Antrobus, R. & Johnson, L. N. Plk1 activation by Ste20-like kinase (Slk) phosphorylation and polo-box phosphopeptide binding assayed with the substrate translationally controlled tumor protein (TCTP). Biochemistry 47, 3688–3696 (2008).

    CAS  PubMed  Google Scholar 

  107. Qian, Y. W., Erikson, E. & Maller, J. L. Purification and cloning of a protein kinase that phosphorylates and activates the polo-like kinase Plx1. Science 282, 1701–1704 (1998).

    CAS  PubMed  Google Scholar 

  108. Walter, S. A. et al. Stk10, a new member of the polo-like kinase kinase family highly expressed in hematopoietic tissue. J. Biol. Chem. 278, 18221–18228 (2003).

    CAS  PubMed  Google Scholar 

  109. Ellinger-Ziegelbauer, H. et al. Ste20-like kinase (SLK), a regulatory kinase for polo-like kinase (Plk) during the G2/M transition in somatic cells. Genes Cells 5, 491–498 (2000).

    CAS  PubMed  Google Scholar 

  110. Alves, P. S., Godinho, S. A. & Tavares, A. A. The Drosophila orthologue of xPlkk1 is not essential for Polo activation and is necessary for proper contractile ring formation. Exp. Cell Res. 312, 308–321 (2006).

    CAS  PubMed  Google Scholar 

  111. Erikson, E., Haystead, T. A., Qian, Y. W. & Maller, J. L. A feedback loop in the polo-like kinase activation pathway. J. Biol. Chem. 279, 32219–32224 (2004).

    CAS  PubMed  Google Scholar 

  112. Carmena, M. et al. The chromosomal passenger complex activates Polo kinase at centromeres. PLoS Biol. 10, e1001250 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Clay, F. J., Ernst, M. R., Trueman, J. W., Flegg, R. & Dunn, A. R. The mouse Plk gene: structural characterization, chromosomal localization and identification of a processed Plk pseudogene. Gene 198, 329–339 (1997).

    CAS  PubMed  Google Scholar 

  114. Kumagai, A. & Dunphy, W. G. Purification and molecular cloning of Plx1, a Cdc25-regulatory kinase from Xenopus egg extracts. Science 273, 1377–1380 (1996).

    CAS  PubMed  Google Scholar 

  115. Lee, K. S., Grenfell, T. Z., Yarm, F. R. & Erikson, R. L. Mutation of the polo-box disrupts localization and mitotic functions of the mammalian polo kinase Plk. Proc. Natl Acad. Sci. USA 95, 9301–9306 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Lee, K. S., Song, S. & Erikson, R. L. The polo-box-dependent induction of ectopic septal structures by a mammalian polo kinase, plk, in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 96, 14360–14365 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Seong, Y. S. et al. A spindle checkpoint arrest and a cytokinesis failure by the dominant-negative polo-box domain of Plk1 in U-2 OS cells. J. Biol. Chem. 277, 32282–32293 (2002).

    CAS  PubMed  Google Scholar 

  118. Song, S. & Lee, K. S. A novel function of Saccharomyces cerevisiae CDC5 in cytokinesis. J. Cell Biol. 152, 451–469 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Sonnhammer, E. L., Eddy, S. R., Birney, E., Bateman, A. & Durbin, R. Pfam: multiple sequence alignments and HMM-profiles of protein domains. Nucleic Acids Res. 26, 320–322 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Lowery, D. M., Lim, D. & Yaffe, M. B. Structure and function of Polo-like kinases. Oncogene 24, 248–259 (2005).

    CAS  PubMed  Google Scholar 

  121. Lowery, D. M. et al. Proteomic screen defines the Polo-box domain interactome and identifies Rock2 as a Plk1 substrate. EMBO J. 26, 2262–2273 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Davis, F. M., Tsao, T. Y., Fowler, S. K. & Rao, P. N. Monoclonal antibodies to mitotic cells. Proc. Natl Acad. Sci. USA 80, 2926–2930 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Westendorf, J. M., Rao, P. N. & Gerace, L. Cloning of cDNAs for M-phase phosphoproteins recognized by the MPM2 monoclonal antibody and determination of the phosphorylated epitope. Proc. Natl Acad. Sci. USA 91, 714–718 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Golan, A., Yudkovsky, Y. & Hershko, A. The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1–cyclin B and Plk. J. Biol. Chem. 277, 15552–15557 (2002).

    CAS  PubMed  Google Scholar 

  125. Zhang, F., Fan, Q., Ren, K. & Andreassen, P. R. PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol. Cancer Res. 7, 1110–1118 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Soung, N. K. et al. Plk1-dependent and -independent roles of an ODF2 splice variant, hCenexin1, at the centrosome of somatic cells. Dev. Cell 16, 539–550 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Yamaguchi, T. et al. Phosphorylation by Cdk1 induces Plk1-mediated vimentin phosphorylation during mitosis. J. Cell Biol. 171, 431–436 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kishi, K., van Vugt, M. A., Okamoto, K., Hayashi, Y. & Yaffe, M. B. Functional dynamics of Polo-like kinase 1 at the centrosome. Mol. Cell. Biol. 29, 3134–3150 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Hanisch, A., Wehner, A., Nigg, E. A. & Sillje, H. H. Different Plk1 functions show distinct dependencies on Polo-box domain-mediated targeting. Mol. Biol. Cell 17, 448–459 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Kang, Y. H. et al. Self-regulated Plk1 recruitment to kinetochores by the Plk1–PBIP1 interaction is critical for proper chromosome segregation. Mol. Cell 24, 409–422 (2006).

    CAS  PubMed  Google Scholar 

  131. Lee, K. S., Oh, D. Y., Kang, Y. H. & Park, J. E. Self-regulated mechanism of Plk1 localization to kinetochores: lessons from the Plk1–PBIP1 interaction. Cell Div. 3, 4 (2008).

    PubMed  PubMed Central  Google Scholar 

  132. Neef, R. et al. Choice of Plk1 docking partners during mitosis and cytokinesis is controlled by the activation state of Cdk1. Nature Cell Biol. 9, 436–444 (2007).

    CAS  PubMed  Google Scholar 

  133. Neef, R. et al. Phosphorylation of mitotic kinesin-like protein 2 by polo-like kinase 1 is required for cytokinesis. J. Cell Biol. 162, 863–875 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Smits, V. A. et al. Polo-like kinase-1 is a target of the DNA damage checkpoint. Nature Cell Biol. 2, 672–676 (2000).

    CAS  PubMed  Google Scholar 

  135. Tsvetkov, L., Xu, X., Li, J. & Stern, D. F. Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody. J. Biol. Chem. 278, 8468–8475 (2003).

    CAS  PubMed  Google Scholar 

  136. Liu, X. & Erikson, R. L. Activation of Cdc2/cyclin B and inhibition of centrosome amplification in cells depleted of Plk1 by siRNA. Proc. Natl Acad. Sci. USA 99, 8672–8676 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. van Vugt, M. A., Bras, A. & Medema, R. H. Polo-like kinase-1 controls recovery from a G2 DNA damage-induced arrest in mammalian cells. Mol. Cell 15, 799–811 (2004). Demonstrates that the mitotic machinery is reset after DNA damage and uses RNAi to show that that PLK1 activity is required for exit from the DNA damage-induced G2 checkpoint. Shows a requirement for CDC25B, but not CDC25A or CDC25C, for mitotic re-entry.

    CAS  PubMed  Google Scholar 

  138. Nasmyth, K. How do so few control so many? Cell 120, 739–746 (2005).

    CAS  PubMed  Google Scholar 

  139. Skowyra, D., Craig, K. L., Tyers, M., Elledge, S. J. & Harper, J. W. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 91, 209–219 (1997). This classic paper reconstitutes the yeast Skp1–Cdc53–Cdc4 E3 ubiquitin ligase machinery and shows that the F-box protein Cdc4 is a WD40 repeat-containing phospho-Ser/Thr-binding module that recognizes only the phosphorylated form of its substrate, Sic1. Substitution of Cdc4 with another F-box protein, Grr1, results in phospho-dependent binding to the yeast G1 cyclins Cln1 and Cln2 rather than Sic1. This indicates that F-box proteins are phospho-dependent binding domains with unique substrate specificities.

    CAS  PubMed  Google Scholar 

  140. Skaar, J. R., Pagan, J. K. & Pagano, M. Mechanisms and function of substrate recruitment by F-box proteins. Nature Rev. Mol. Cell Biol. 14, 369–381 (2013).

    CAS  Google Scholar 

  141. Schulman, B. A. et al. Insights into SCF ubiquitin ligases from the structure of the Skp1–Skp2 complex. Nature 408, 381–386 (2000).

    CAS  PubMed  Google Scholar 

  142. Cardozo, T. & Pagano, M. The SCF ubiquitin ligase: insights into a molecular machine. Nature Rev. Mol. Cell Biol. 5, 739–751 (2004).

    CAS  Google Scholar 

  143. Amati, B. & Vlach, J. Kip1 meets SKP2: new links in cell-cycle control. Nature Cell Biol. 1, E91–E93 (1999).

    CAS  PubMed  Google Scholar 

  144. Bornstein, G. et al. Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J. Biol. Chem. 278, 25752–25757 (2003).

    CAS  PubMed  Google Scholar 

  145. Yu, Z. K., Gervais, J. L. & Zhang, H. Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21CIP1/WAF1 and cyclin D proteins. Proc. Natl Acad. Sci. USA 95, 11324–11329 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Koepp, D. M. et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFBW7 ubiquitin ligase. Science 294, 173–177 (2001).

    CAS  PubMed  Google Scholar 

  147. Strohmaier, H. et al. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 413, 316–322 (2001).

    CAS  PubMed  Google Scholar 

  148. Spruck, C. et al. A CDK-independent function of mammalian Cks1: targeting of SCFSkp2 to the CDK inhibitor p27Kip1. Mol. Cell 7, 639–650 (2001).

    CAS  PubMed  Google Scholar 

  149. Ganoth, D. et al. The cell-cycle regulatory protein Cks1 is required for SCFSkp2-mediated ubiquitinylation of p27. Nature Cell Biol. 3, 321–324 (2001).

    CAS  PubMed  Google Scholar 

  150. Bourne, Y. et al. Crystal structure and mutational analysis of the human CDK2 kinase complex with cell cycle-regulatory protein CksHs1. Cell 84, 863–874 (1996).

    CAS  PubMed  Google Scholar 

  151. Hao, B. et al. Structural basis of the Cks1-dependent recognition of p27Kip1 by the SCFSkp2 ubiquitin ligase. Mol. Cell 20, 9–19 (2005).

    CAS  PubMed  Google Scholar 

  152. Bashir, T., Dorrello, N. V., Amador, V., Guardavaccaro, D. & Pagano, M. Control of the SCFSkp2–Cks1 ubiquitin ligase by the APC/CCdh1 ubiquitin ligase. Nature 428, 190–193 (2004).

    CAS  PubMed  Google Scholar 

  153. Wei, W. et al. Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 428, 194–198 (2004). Shows, together with reference 152, a feedback loop between the phospho-dependent SCFSKP2 ubiquitin ligase that degrades the G1–S regulators p27 and p21, and the CDH1-containing APC/C. Ubiquitin-mediated destruction of the SKP2–CKS1 SCF E3 ligase by the APC/C in late M and G1 allows the CDK inhibitors p27 and p21 to accumulate, thereby maintaining the G1 state and preventing inappropriate S phase entry.

    CAS  PubMed  Google Scholar 

  154. Hsu, J. Y., Reimann, J. D., Sorensen, C. S., Lukas, J. & Jackson, P. K. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1. Nature Cell Biol. 4, 358–366 (2002).

    CAS  PubMed  Google Scholar 

  155. Reimann, J. D. et al. Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. Cell 105, 645–655 (2001).

    CAS  PubMed  Google Scholar 

  156. Mueller, P. R., Coleman, T. R. & Dunphy, W. G. Cell cycle regulation of a Xenopus Wee1-like kinase. Mol. Biol. Cell 6, 119–134 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Moberg, K. H., Bell, D. W., Wahrer, D. C., Haber, D. A. & Hariharan, I. K. Archipelago regulates cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413, 311–316 (2001).

    CAS  PubMed  Google Scholar 

  158. Jin, J. et al. SCFβ-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev. 17, 3062–3074 (2003). Shows that multisite phosphorylation of CDC25A by CHK1, together with other unidentified kinases, generates a non-canonical phosphodegron motif that is recognized by the WD40 repeat-containing phospho-Ser/Thr-binding protein βTrCP, resulting in degradation of the cell cycle regulator CDC25A.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Frescas, D. & Pagano, M. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. Nature Rev. Cancer 8, 438–449 (2008).

    CAS  Google Scholar 

  160. Watanabe, N. et al. Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways. Proc. Natl Acad. Sci. USA 102, 11663–11668 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Watanabe, N. et al. M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFβ-TrCP. Proc. Natl Acad. Sci. USA 101, 4419–4424 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Kumagai, A. & Dunphy, W. G. Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts. Mol. Cell 6, 839–849 (2000). Identifies claspin as a CHK1-binding protein that is required for CHK1 activation and G2–M arrest by damaged DNA and synthetic oligonucleotides that mimic stalled replication forks.

    CAS  PubMed  Google Scholar 

  163. Mailand, N., Bekker-Jensen, S., Bartek, J. & Lukas, J. Destruction of Claspin by SCFβ-TrCP restrains Chk1 activation and facilitates recovery from genotoxic stress. Mol. Cell 23, 307–318 (2006).

    CAS  PubMed  Google Scholar 

  164. Busino, L. et al. Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage. Nature 426, 87–91 (2003).

    CAS  PubMed  Google Scholar 

  165. Reinhardt, H. C., Aslanian, A. S., Lees, J. A. & Yaffe, M. B. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 11, 175–189 (2007). Identifies a third DNA damage checkpoint pathway that operates independently of the ATM–CHK2 and ATR–CHK1 pathways and is specifically required only in cells that lack functional p53. The ultimate effector kinase for this pathway is MK2, the substrates of which partially overlap with those of CHK1 and CHK2.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Sorensen, C. S. et al. Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell 3, 247–258 (2003).

    CAS  PubMed  Google Scholar 

  167. Kang, T. et al. GSK-3β targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3β inactivation correlates with Cdc25A overproduction in human cancers. Cancer Cell 13, 36–47 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. Brca1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999).

    CAS  PubMed  Google Scholar 

  169. Scully, R., Xie, A. & Nagaraju, G. Molecular functions of BRCA1 in the DNA damage response. Cancer Biol. Ther. 3, 521–527 (2004).

    CAS  PubMed  Google Scholar 

  170. Snouwaert, J. N. et al. BRCA1 deficient embryonic stem cells display a decreased homologous recombination frequency and an increased frequency of non-homologous recombination that is corrected by expression of a brca1 transgene. Oncogene 18, 7900–7907 (1999).

    CAS  PubMed  Google Scholar 

  171. Venkitaraman, A. R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108, 171–182 (2002).

    CAS  PubMed  Google Scholar 

  172. Zhang, H., Fang, Y., Huang, C., Yang, X. & Ye, Q. Human pescadillo induces large-scale chromatin unfolding. Sci. China C Life Sci. 48, 270–276 (2005).

    CAS  PubMed  Google Scholar 

  173. Le Page, F. et al. BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res. 60, 5548–5552 (2000).

    CAS  PubMed  Google Scholar 

  174. Hartman, A. R. & Ford, J. M. BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair. Nature Genet. 32, 180–184 (2002).

    CAS  PubMed  Google Scholar 

  175. Bhattacharyya, A., Ear, U. S., Koller, B. H., Weichselbaum, R. R. & Bishop, D. K. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J. Biol. Chem. 275, 23899–23903 (2000).

    CAS  PubMed  Google Scholar 

  176. Scully, R. et al. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90, 425–435 (1997).

    CAS  PubMed  Google Scholar 

  177. Xia, B. et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nature Genet. 39, 159–161 (2007).

    CAS  PubMed  Google Scholar 

  178. Zhong, Q. et al. Association of BRCA1 with the hRad50–hMre11–p95 complex and the DNA damage response. Science 285, 747–750 (1999).

    CAS  PubMed  Google Scholar 

  179. Moynahan, M. E., Cui, T. Y. & Jasin, M. Homology-directed DNA repair, mitomycin-C resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res. 61, 4842–4850 (2001).

    CAS  PubMed  Google Scholar 

  180. Narod, S. A. & Foulkes, W. D. BRCA1 and BRCA2: 1994 and beyond. Nature Rev. Cancer 4, 665–676 (2004).

    CAS  Google Scholar 

  181. Patel, K. J. et al. Involvement of Brca2 in DNA repair. Mol. Cell 1, 347–357 (1998).

    CAS  PubMed  Google Scholar 

  182. Fujiwara, T. et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043–1047 (2005). Shows that in response to drug-induced cytokinesis failure, p53-deficient tetraploid cells develop gross chromosomal rearrangements, suggesting that tetraploidization precedes aneuploidy. These tetraploid p53 -null cells were transformed by brief exposure to a carcinogen, and formed tumours when implanted into nude mice

    CAS  PubMed  Google Scholar 

  183. Botuyan, M. V. et al. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 127, 1361–1373 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Huyen, Y. et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406–411 (2004).

    CAS  PubMed  Google Scholar 

  185. Lehmann, A. R. Duplicated region of sequence similarity to the human XRCC1 DNA repair gene in the Schizosaccharomyces pombe rad4/cut5 gene. Nucleic Acids Res. 21, 5274 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Zhang, X. et al. Structure of an XRCC1 BRCT domain: a new protein–protein interaction module. EMBO J. 17, 6404–6411 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Masson, M. et al. XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol. Cell. Biol. 18, 3563–3571 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Tomkinson, A. E. & Mackey, Z. B. Structure and function of mammalian DNA ligases. Mutat. Res. 407, 1–9 (1998).

    CAS  PubMed  Google Scholar 

  189. Yu, X., Wu, L. C., Bowcock, A. M., Aronheim, A. & Baer, R. The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J. Biol. Chem. 273, 25388–25392 (1998).

    CAS  PubMed  Google Scholar 

  190. Joo, W. S. et al. Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure. Genes Dev. 16, 583–593 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Manke, I. A., Lowery, D. M., Nguyen, A. & Yaffe, M. B. BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 302, 636–639 (2003).

    CAS  PubMed  Google Scholar 

  192. Yu, X., Chini, C. C., He, M., Mer, G. & Chen, J. The BRCT domain is a phospho-protein binding domain. Science 302, 639–642 (2003). References 191 and 192 identify BRCT domains as phospho-Ser/Thr-binding domains. Reference 191 identifies the BRCT domains in PTIP and BRCA1 as phospho-Ser/Thr-binding modules that recognize substrates phosphorylated by the DDR kinases ATM and ATR in response to genotoxic stress. Reference 192 demonstrates that the BRCA1 BRCT domain directly interacts with BACH1 in a phosphorylation-dependent manner and also identifies the BRCT domains from other proteins as phosphopeptide-binding modules.

    CAS  PubMed  Google Scholar 

  193. Cantor, S. B. et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105, 149–160 (2001). Demonstrates that BACH1 binds directly to the BRCT repeats of BRCA1. Furthermore, germline mutations in the helicase domain of BACH1 were detected in two early-onset breast cancer patients.

    CAS  PubMed  Google Scholar 

  194. Clapperton, J. A. et al. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nature Struct. Mol. Biol. 11, 512–518 (2004).

    CAS  Google Scholar 

  195. Botuyan, M. V. et al. Structural basis of BACH1 phosphopeptide recognition by BRCA1 tandem BRCT domains. Structure 12, 1137–1146 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Munoz, I. M., Jowsey, P. A., Toth, R. & Rouse, J. Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage. Nucleic Acids Res. 35, 5312–5322 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Jowsey, P. A., Doherty, A. J. & Rouse, J. Human PTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionizing radiation. J. Biol. Chem. 279, 55562–55569 (2004).

    CAS  PubMed  Google Scholar 

  198. Rodriguez, M., Yu, X., Chen, J. & Songyang, Z. Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains. J. Biol. Chem. 278, 52914–52918 (2003).

    CAS  PubMed  Google Scholar 

  199. Stucki, M. et al. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123, 1213–1226 (2005). Shows that MDC1 directly binds to γH2AX via its BRCT repeats. The authors show that MDC1–γH2AX complex formation regulates H2AX phosphorylation and is crucial for proper recruitment of additional DDR proteins to the sites of DNA lesions.

    CAS  PubMed  Google Scholar 

  200. Xiao, A. et al. WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature 457, 57–62 (2009).

    CAS  PubMed  Google Scholar 

  201. Lee, J., Kumagai, A. & Dunphy, W. G. The Rad9-Hus1–Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR. J. Biol. Chem. 282, 28036–28044 (2007).

    CAS  PubMed  Google Scholar 

  202. Kumagai, A., Lee, J., Yoo, H. Y. & Dunphy, W. G. TopBP1 activates the ATR–ATRIP complex. Cell 124, 943–955 (2006). Demonstrates that TOPBP1 induces the kinase activity of ATR. The ATR-activating domain lies outside of its numerous BRCT repeats.

    CAS  PubMed  Google Scholar 

  203. Delacroix, S., Wagner, J. M., Kobayashi, M., Yamamoto, K. & Karnitz, L. M. The Rad9–Hus1–Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1. Genes Dev. 21, 1472–1477 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Rappas, M., Oliver, A. W. & Pearl, L. H. Structure and function of the Rad9-binding region of the DNA-damage checkpoint adaptor TopBP1. Nucleic Acids Res. 39, 313–324 (2011).

    CAS  PubMed  Google Scholar 

  205. Hofmann, K. & Bucher, P. The FHA domain: a putative nuclear signalling domain found in protein kinases and transcription factors. Trends Biochem. Sci. 20, 347–349 (1995).

    CAS  PubMed  Google Scholar 

  206. Mohammad, D. H. & Yaffe, M. B. 14-3-3 proteins, FHA domains and BRCT domains in the DNA damage response. DNA Repair (Amst.) 8, 1009–1017 (2009).

    CAS  Google Scholar 

  207. Durocher, D. et al. The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phosphodependent signaling mechanisms. Mol. Cell 6, 1169–1182 (2000). Oriented peptide library screening was used to define the optimal phosphopeptide-binding motifs recognized by a series of FHA domains, including those present in the CHK2 homologue Rad53p. The structural basis for phospho-specificity was defined by solving the X-ray crystal structure of a Rad53p FHA domain–phosphopeptide complex.

    CAS  PubMed  Google Scholar 

  208. Ding, Z. et al. PhosphoThr peptide binding globally rigidifies much of the FHA domain from Arabidopsis receptor kinase-associated protein phosphatase. Biochemistry 44, 10119–10134 (2005).

    CAS  PubMed  Google Scholar 

  209. Yaffe, M. B. & Smerdon, S. J. The use of in vitro peptide-library screens in the analysis of phosphoserine/threonine-binding domain structure and function. Annu. Rev. Biophys. Biomol. Struct. 33, 225–244 (2004).

    CAS  PubMed  Google Scholar 

  210. Kastan, M. B. & Lim, D. S. The many substrates and functions of ATM. Nature Rev. Mol. Cell Biol. 1, 179–186 (2000).

    CAS  Google Scholar 

  211. Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S. & Bonner, W. M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).

    CAS  PubMed  Google Scholar 

  212. Harper, J. W. & Elledge, S. J. The DNA damage response: ten years after. Mol. Cell 28, 739–745 (2007).

    CAS  PubMed  Google Scholar 

  213. Schwarz, J. K., Lovly, C. M. & Piwnica-Worms, H. Regulation of the Chk2 protein kinase by oligomerization-mediated cis- and trans-phosphorylation. Mol. Cancer Res. 1, 598–609 (2003).

    CAS  PubMed  Google Scholar 

  214. Melchionna, R., Chen, X. B., Blasina, A. & McGowan, C. H. Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1. Nature Cell Biol. 2, 762–765 (2000).

    CAS  PubMed  Google Scholar 

  215. Ahn, J. Y., Schwarz, J. K., Piwnica-Worms, H. & Canman, C. E. Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation. Cancer Res. 60, 5934–5936 (2000).

    CAS  PubMed  Google Scholar 

  216. Bartek, J., Falck, J. & Lukas, J. CHK2 kinase — a busy messenger. Nature Rev. Mol. Cell Biol. 2, 877–886 (2001).

    CAS  Google Scholar 

  217. Li, J. et al. Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2. Mol. Cell 9, 1045–1054 (2002).

    CAS  PubMed  Google Scholar 

  218. Ahn, J. Y., Li, X., Davis, H. L. & Canman, C. E. Phosphorylation of threonine 68 promotes oligomerization and autophosphorylation of the Chk2 protein kinase via the forkhead-associated domain. J. Biol. Chem. 277, 19389–19395 (2002).

    CAS  PubMed  Google Scholar 

  219. Lee, C. H. & Chung, J. H. The hCds1 (Chk2)-FHA domain is essential for a chain of phosphorylation events on hCds1 that is induced by ionizing radiation. J. Biol. Chem. 276, 30537–30541 (2001).

    CAS  PubMed  Google Scholar 

  220. Xu, X., Tsvetkov, L. M. & Stern, D. F. Chk2 activation and phosphorylation-dependent oligomerization. Mol. Cell. Biol. 22, 4419–4432 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Cai, Z., Chehab, N. H. & Pavletich, N. P. Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase. Mol. Cell 35, 818–829 (2009).

    CAS  PubMed  Google Scholar 

  222. Lee, M. S., Edwards, R. A., Thede, G. L. & Glover, J. N. Structure of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the γ-H2AX histone tail. J. Biol. Chem. 280, 32053–32056 (2005).

    CAS  PubMed  Google Scholar 

  223. Lou, Z. et al. MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol. Cell 21, 187–200 (2006).

    CAS  PubMed  Google Scholar 

  224. Matsuoka, S. et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160–1166 (2007).

    CAS  PubMed  Google Scholar 

  225. Mailand, N. et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131, 887–900 (2007).

    CAS  PubMed  Google Scholar 

  226. Kolas, N. K. et al. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science 318, 1637–1640 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Huen, M. S. et al. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 131, 901–914 (2007). References 225–227 show that the FHA and RING domain-containing protein RNF8 mediates recruitment of BRCA1 and 53BP1 to DNA lesions. This is mediated by phospho-dependent FHA domain-mediated binding of RNF8 to MDC1 and RNF8-dependent ubiquitylation of H2AX. Furthermore, RNF8-depleted cells showed an increased sensitivity to ionizing radiation.

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Wang, B. et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316, 1194–1198 (2007). Identifies Abraxas as a protein that interacts with the BRCA1 BRCT repeat in a manner that is mutually exclusive with its binding to BACH1 and CtIP. Furthermore, Abraxas was shown to recruit RAP80 to BRCA1 and both Abraxas and RAP80 were crucial for DNA damage resistance and DNA repair.

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Doil, C. et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 136, 435–446 (2009).

    CAS  PubMed  Google Scholar 

  230. Devgan, S. S. et al. Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia. Cell Death Differ. 18, 1500–1506 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Stewart, G. S., Wang, B., Bignell, C. R., Taylor, A. M. & Elledge, S. J. MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421, 961–966 (2003). Reports that H2AX is required for the recruitment of MDC1 into DNA damage-induced nuclear foci. Furthermore, MDC1is shown to bind to H2AX in a matter that depends on H2AX phosphorylation. Demonstrates that MDC1 depletion increases the cellular sensitivity to ionizing radiation and that MDC1 controls the formation of DNA damage-induced nuclear 53BP1-, BRCA1- and MRN foci.

    CAS  PubMed  Google Scholar 

  232. Lou, Z., Minter-Dykhouse, K., Wu, X. & Chen, J. MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Nature 421, 957–961 (2003). MDC1 localizes to sites of DNA breaks and associates with Thr68 phosphorylated CHK2 after DNA damage in a manner dependent on the FHA domain of MDC1. Shows that MDC1 is phosphorylated in an ATM–CHK2-dependent manner after genotoxic stress. MDC1 depletion results in S-phase checkpoint failure and apoptosis resistance following DNA damage.

    CAS  PubMed  Google Scholar 

  233. Goldberg, M. et al. MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature 421, 952–956 (2003). Reports that MDC1 is hyperphosphorylated in an ATM-dependent manner and that MDC1 is recruited into nuclear foci containing the MRN complex, γH2AX and 53BP1. MDC1 depletion is shown to prevent the DNA damage-induced recruitment of the MRN complex into nuclear foci. Overexpression of the isolated MDC1 FHA domain reduces focus formation by MDC1 and the MRN complex and induces radioresistant DNA synthesis, suggesting that MDC1 is crucial for the activation of the intra-S-phase checkpoint.

    CAS  PubMed  Google Scholar 

  234. Spycher, C. et al. Constitutive phosphorylation of MDC1 physically links the MRE11–RAD50–NBS1 complex to damaged chromatin. J. Cell Biol. 181, 227–240 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Melander, F. et al. Phosphorylation of SDT repeats in the MDC1 N terminus triggers retention of NBS1 at the DNA damage-modified chromatin. J. Cell Biol. 181, 213–226 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Durocher, D., Henckel, J., Fersht, A. R. & Jackson, S. P. The FHA domain is a modular phosphopeptide recognition motif. Mol. Cell 4, 387–394 (1999). Demonstrates that the two distinct FHA domains of the Saccharomyces cerevisiae CHK2 homologue Rad53p possess phosphopeptide-binding specificity. Identifies four additional FHA domains from prokaryotic and eukaryotic organisms as phosphopeptide-binding modules in vitro.

    CAS  PubMed  Google Scholar 

  237. Williams, R. S. et al. Nbs1 flexibly tethers Ctp1 and Mre11–Rad50 to coordinate DNA double-strand break processing and repair. Cell 139, 87–99 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Bernstein, N. K. et al. The molecular architecture of the mammalian DNA repair enzyme, polynucleotide kinase. Mol. Cell 17, 657–670 (2005).

    CAS  PubMed  Google Scholar 

  239. Lloyd, J. et al. A supramodular FHA/BRCT-repeat architecture mediates Nbs1 adaptor function in response to DNA damage. Cell 139, 100–111 (2009). Provides the crystal structure of the N-terminal region of NBS1, showing that the FHA domain and BRCT repeat domains of NBS1 structurally function as a single unit. Demonstrate that pSer-Asp-pThr-Asp motifs in MDC1 serve as binding motifs for NBS1, and that NBS1 binding to MDC1 requires both the NBS1 FHA domain and BRCT repeats.

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Chapman, J. R. & Jackson, S. P. Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. EMBO Rep. 9, 795–801 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Li, M. et al. Solution structure of the Set2–Rpb1 interacting domain of human Set2 and its interaction with the hyperphosphorylated C-terminal domain of Rpb1. Proc. Natl Acad. Sci. USA 102, 17636–17641 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Smith, M. J., Kulkarni, S. & Pawson, T. FF domains of CA150 bind transcription and splicing factors through multiple weak interactions. Mol. Cell. Biol. 24, 9274–9285 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Gurevich, V. V., Gurevich, E. V. & Cleghorn, W. M. Arrestins as multi-functional signaling adaptors. Handb. Exp. Pharmacol. 186, 15–37 (2008).

    CAS  Google Scholar 

  244. Reindl, W., Yuan, J., Kramer, A., Strebhardt, K. & Berg, T. Inhibition of polo-like kinase 1 by blocking polo-box domain-dependent protein-protein interactions. Chem. Biol. 15, 459–466 (2008).

    CAS  PubMed  Google Scholar 

  245. Nguyen, A., Rothman, D. M., Stehn, J., Imperiali, B. & Yaffe, M. B. Caged phosphopeptides reveal a temporal role for 14-3-3 in G1 arrest and S-phase checkpoint function. Nature Biotechnol. 22, 993–1000 (2004).

    CAS  Google Scholar 

  246. Dong, S. et al. 14-3-3 integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198–FGFR1-transformed hematopoietic cells. Blood 110, 360–369 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Elia, E. A. H. et al. The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain. Cell 115, 83–95 (2003). Reveals the crystal structure of a human PLK1 PBD–phosphopeptide complex. PBD mutations that prevent phosphopeptide binding eliminate targeting of the PLK1 PBD to centrosomes in prophase. Furthermore, phosphopeptide binding to the PBD stimulates PLK1 kinase activity, suggesting a conformational switching mechanism for PLK regulation.

    CAS  PubMed  Google Scholar 

  248. Wu, G. et al. Structure of a β-TrCP1–Skp1–β-catenin complex: destruction motif binding and lysine specificity of the SCFβ-TrCP1 ubiquitin ligase. Mol. Cell 11, 1445–1456 (2003). Provides the crystal structure of the βTrCP1–SKP1-β-catenin complex and reveals the basis for phosphorylation-dependent substrate recognition by the βTrCP1 WD40 domain.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors apologize to their colleagues for the omission of many seminal contributions to the field, and their corresponding references, owing to space constraints. They gratefully acknowledge S. J. Smerdon, their long-standing collaborator, for his continual insights and encouragement in these projects. This work was supported by the US National Institutes of Health (GM68762, CA112967, ES015339, and ES020466 to M.B.Y.), the Volkswagenstiftung (Lichtenberg Program; to H.C.R.), the Deutsche Forschungsgemeinschaft (KFO-286, SFB-832, SFB-829, RE2246/2-1; to H.C.R.), the Helmholtz-Gemeinschaft (Preclinical Comprehensive Cancer Center; to H.C.R.), the Deutsche Jose Carreras Stiftung (DJCLS-R12/26 to H.C.R) and the David H. Koch Fund (H.C.R. and M.B.Y.).

Author information

Authors and Affiliations

  1. Departments of Biology and Biological Engineering, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    H. Christian Reinhardt & Michael B. Yaffe

  2. Division of Hematology and Oncology, University Hospital of Cologne, Center for Internal Medicine, Cologne, 50937, Germany

    H. Christian Reinhardt

  3. Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases, Weyertal 115b, Cologne, Germany

    H. Christian Reinhardt

  4. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Michael B. Yaffe

Authors
  1. H. Christian Reinhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael B. Yaffe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael B. Yaffe.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (figure)

A diverse array of cellular functions regulated through 14-3-3 binding. (PDF 332 kb)

Supplementary information S2 (box)

Structural information on the WW, PBD and BRCT phosphoSer/Thr binding domains (PDF 243 kb)

PowerPoint slides

Glossary

Cap-dependent mRNA translation

Describes a process by which mRNA translation is initiated through the recruitment of 40S ribosomes to the 5′ 7-methylguanosine-capped end of mRNAs via eukaryotic translation initiation factor 4F (eIF4F).

Cap-independent mRNA translation

Describes a process of mRNA translation by which the requirement for the 5′ 7-methylguanosine cap and eukaryotic translation initiation factor 4E (eIF4E) is bypassed, and translation initiation occurs instead through ribosome recruitment to internal ribosomal entry sites (IRESs).

Midbody

A dense protein structure that represents the remnant of the spindle midzone located at the centre of the narrow membranous bridge connecting two dividing cells at the end of cytokinesis.

Centralspindlin

A protein complex consisting of MKLP1 (mitotic kinesin-like protein 1) and CYK4 (cytokinesis defect 4) that controls mitosis through various mechanisms, including initiation of central spindle assembly, positioning of the division plane and regulation of midbody assembly and abscission.

Spindle midzone

A region of the anaphase spindle that is composed of overlapping antiparallel microtubules from opposite spindle poles. It is also known as the central spindle.

Intra-S phase checkpoint

ATM (ataxia-telangiectasia mutated)- and ATR-dependent, transient inhibition of DNA replication in response to DNA damage. Defects in an ionizing radiation-induced intra-S phase checkpoint cause radioresistant DNA synthesis.

K m

(Michaelis constant). An intrinsic property of enzymes that describes the concentration for a particular substrate at which the enzyme works at half-maximal capacity, that is, at Vmax/2.

Spindle checkpoint

A mechanism that detects unattached kinetochores in mitosis and arrests the cell cycle in metaphase, prior to anaphase onset.

E3 ubiquitin ligases

These ligases facilitate the transfer of ubiquitin from a ubiquitin conjugating enzyme (E2) to Lys residues on a substrate, often forming polyubiquitin chains that target the substrate for degradation by the proteasome.

Homologous recombination-mediated DSB repair

A DNA recombination pathway that includes the repair of DNA double-strand breaks (DSBs). This pathway involves the resection of one strand of the DNA in the vicinity of the break followed by use of a homologous double-stranded DNA molecule as a template for the repair of the broken DNA.

Nucleotide excision repair

This repair pathway is used to remove the vast majority of lesions located on a DNA single strand, including lesions caused by ultraviolet (UV) light and cisplatin damage. This pathway involves the enzymatic excision of one or more nucleotides from the damaged DNA single strand followed by new DNA synthesis using the opposing strand as a template.

Non-homologous end-joining

(NHEJ). The main DNA repair pathway used throughout the cell cycle to repair chromosomal double-strand DNA breaks in somatic cells, involving the fusion of the two broken DNA ends. In contrast to homologous recombination-mediated repair, NHEJ is error-prone because it leads to the joining of heterologous ends, often with the loss of intervening genetic material in the region of the break.

Base excision repair

(BER). A DNA repair pathway in which a damaged DNA base within a single DNA strand is initially removed by a glycosylase enzyme and the abasic nucleotide is then replaced, along with a short patch of adjacent nucleotides.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reinhardt, H., Yaffe, M. Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response. Nat Rev Mol Cell Biol 14, 563–580 (2013). https://doi.org/10.1038/nrm3640

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3640

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing