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Chk2 kinase — a busy messenger

Key Points

  • To protect genome integrity, eukaryotic cells possess evolutionarily conserved surveillance mechanisms that are termed checkpoints, which constantly monitor the status and quality of chromosomal DNA and delay cell-cycle progression in response to replication stress or various types of DNA damage.

  • The recent cloning of mammalian Chk2, a protein kinase that is homologous to yeast Rad53/cds1, has sparked an avalanche of exciting research, which shows the essential role of Chk2 in transmitting checkpoint signals from upstream detectors of DNA lesions to cell-cycle effectors and the DNA-repair machinery.

  • The overall structure of Chk2 is remarkably conserved throughout evolution, which is consistent with its involvement in cellular processes of general importance. Phosphorylation of the amino-terminal regulatory region of Chk2 by the upstream ATM/ATR kinases, autophosphorylation within the carboxy-terminal kinase domain, and protein?protein interactions that are mediated by the central forkhead-associated (FHA) domain showed exciting insights into the complexity of molecular events during the early cellular response to genotoxic stress.

  • The growing number of Chk2 targets include the cell-cycle-regulating Cdc25A and Cdc25C phosphatases, and the tumour suppressors p53 and BRCA1. By phosphorylating these (and presumably other) effector proteins, Chk2 links the early checkpoint events with cell-cycle arrest in the G1, S and G2 phases, activation of DNA repair or, in some cases, programmed cell death.

  • Analysis of different human tissues using newly developed antibodies showed an unexpected correlation of Chk2 expression with tissue biology, which indicates that as well as guarding against genetic instability in proliferating cells, Chk2 might also have an important function in propagating DNA-damage signals in quiescent and/or differentiated tissues.

  • The identification of Chk2 mutations in different human cancer types and the subsequent biochemical analyses of the tumour-associated Chk2 alleles qualify Chk2 as a novel tumour suppressor and open up unprecedented possibilities in the search for a new generation of drugs for cancer therapy.

Abstract

Checkpoint kinase 2 (Chk2) is emerging as a key mediator of diverse cellular responses to genotoxic stress, guarding the integrity of the genome throughout eukaryotic evolution. Recent studies show the fundamental role of Chk2 in the network of genome-surveillance pathways that coordinate cell-cycle progression with DNA repair and cell survival or death. Defects in Chk2 contribute to the development of both hereditary and sporadic human cancers, and earmark this kinase as a candidate tumour suppressor and an attractive target for drug discovery.

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Figure 1: Cell-cycle checkpoints.
Figure 2: Chk2 in evolution.
Figure 3: CHK2 genomic and protein structure.
Figure 4: Models of Chk2 activation.
Figure 5: Chk2 downstream effectors.
Figure 6: Subcellular localization and tissue biology of human CHK2.
Figure 7: CHK2 as a tumour suppressor.

References

  1. 1

    Elledge, S. J. Cell cycle checkpoints: preventing an identity crisis. Science 274, 1664?1672 (1996).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Weinert, T. DNA damage and checkpoint pathways: molecular anatomy and interactions with repair. Cell 94, 555?558 (1998).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Walworth, N. C. Cell-cycle checkpoint kinases: checking in on the cell cycle. Curr. Opin. Cell Biol. 12, 697?704 (2000).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Hoeijmakers, J. H. Genome maintenance mechanisms for preventing cancer. Nature 411, 366?374 (2001).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Rotman, G. & Shiloh, Y. The ATM gene and protein: possible roles in genome surveillance, checkpoint controls and cellular defence against oxidative stress. Cancer Surv. 29, 285?304 (1997).

    CAS  PubMed  Google Scholar 

  6. 6

    Hartwell, L. H. & Kastan, M. B. Cell cycle control and cancer. Science 266, 1821?1828 (1994).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Hartwell, L. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71, 543?546 (1992).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Weinert, T. Yeast checkpoint controls and relevance to cancer. Cancer Surv. 29, 109?132 (1997).

    CAS  PubMed  Google Scholar 

  9. 9

    Dasika, G. K. et al. DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis. Oncogene 18, 7883?7899 (1999).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Abraham, R. T. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 15, 2177?2196 (2001).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Zhou, B. B. & Elledge, S. J. The DNA damage response: putting checkpoints in perspective. Nature 408, 433?439 (2000).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Lowndes, N. F. & Murguia, J. R. Sensing and responding to DNA damage. Curr. Opin. Genet. Dev. 10, 17?25 (2000).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Durocher, D. & Jackson, S. P. DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr. Opin. Cell Biol. 13, 225?231 (2001).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Khanna, K. K. & Jackson, S. P. DNA double-strand breaks: signaling, repair and the cancer connection. Nature Genet. 27, 247?254 (2001).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Carr, A. M. Control of cell cycle arrest by the Mec1sc/Rad3sp DNA structure checkpoint pathway. Curr. Opin. Genet. Dev. 7, 93?98 (1997).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Murray, A. W. The genetics of cell cycle checkpoints. Curr. Opin. Genet. Dev. 5, 5?11 (1995).

    CAS  Article  PubMed  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 18

    Shiloh, Y. ATM and ATR: networking cellular responses to DNA damage. Curr. Opin. Genet. Dev. 11, 71?77 (2001).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Shiloh, Y. & Rotman, G. Ataxia-telangiectasia and the ATM gene: linking neurodegeneration, immunodeficiency, and cancer to cell cycle checkpoints. J. Clin. Immunol. 16, 254?260 (1996).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Lavin, M. F. & Shiloh, Y. The genetic defect in ataxia-telangiectasia. Annu. Rev. Immunol. 15, 177?202 (1997).

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Rhind, N. & Russell, P. Chk1 and Cds1: linchpins of the DNA damage and replication checkpoint pathways. J. Cell Sci. 113, 3889?3896 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Matsuoka, S., Huang, M. & Elledge, S. J. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 282, 1893?1897 (1998).The cloning of human and mouse Chk2 . Together with references 23?26 , this report shows that mammalian Chk2 is a functional homologue of S. cerevisiae Rad53 and S. pombe cds1, and a downstream effector of ATM.

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Blasina, A. et al. A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Curr. Biol. 9, 1?10 (1999).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Brown, A. L. et al. A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage. Proc. Natl Acad. Sci. USA 96, 3745?3750 (1999).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Tominaga, K. et al. Role of human Cds1 (Chk2) kinase in DNA damage checkpoint and its regulation by p53. J. Biol. Chem. 274, 31463?31467 (1999).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Chaturvedi, P. et al. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene 18, 4047?4054 (1999).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Hartwell, L. H. & Weinert, T. A. Checkpoints: controls that ensure the order of cell cycle events. Science 246, 629?634 (1989).

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Allen, J. B., Zhou, Z., Siede, W., Friedberg, E. C. & Elledge, S. J. The SAD1/RAD53 protein kinase controls multiple checkpoints and DNA damage-induced transcription in yeast. Genes Dev. 8, 2401?2415 (1994).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Murakami, H. & Okayama, H. A kinase from fission yeast responsible for blocking mitosis in S phase. Nature 374, 817?819 (1995).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Guo, Z. & Dunphy, W. G. Response of Xenopus Cds1 in cell-free extracts to DNA templates with double-stranded ends. Mol. Biol. Cell 11, 1535?1546 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Higashitani, A. et al. Caenorhabditis elegans Chk2-like gene is essential for meiosis but dispensable for DNA repair. FEBS Lett. 485, 35?39 (2000).

    CAS  Article  PubMed  Google Scholar 

  32. 32

    Oishi, I. et al. Critical role of Caenorhabditis elegans homologs of Cds1 (Chk2)-related kinases in meiotic recombination. Mol. Cell. Biol. 21, 1329?1335 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    MacQueen, A. J. & Villeneuve, A. M. Nuclear reorganization and homologous chromosome pairing during meiotic prophase require C. elegans chk-2. Genes Dev. 15, 1674?1687 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Oishi, I. et al. A novel Drosophila nuclear protein serine/threonine kinase expressed in the germline during its establishment. Mech. Dev. 71, 49?63 (1998).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Rockmill, B. & Roeder, G. S. A meiosis-specific protein kinase homolog required for chromosome synapsis and recombination. Genes Dev. 5, 2392?2404 (1991).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Matsuoka, S. et al. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc. Natl Acad. Sci. USA 97, 10389?10394 (2000).This study and references 37 and 38 provide evidence for direct phosphorylation of Chk2 by the ATM and ATR kinases in vitro . ATM-dependent phosphorylation of threonine 68 was shown to be required for ionizing-radiation-induced Chk2 activation, also in vivo.

    CAS  Article  PubMed  Google Scholar 

  37. 37

    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  Article  PubMed  Google Scholar 

  38. 38

    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 

  39. 39

    Tanaka, K., Boddy, M. N., Chen, X. B., McGowan, C. H. & Russell, P. Threonine-11, phosphorylated by Rad3 and ATM in vitro, is required for activation of fission yeast checkpoint kinase Cds1. Mol. Cell. Biol. 21, 3398?3404 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    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  Article  PubMed  Google Scholar 

  41. 41

    Li, J., Lee, G. I., Van Doren, S. R. & Walker, J. C. The FHA domain mediates phosphoprotein interactions. J. Cell Sci. 113, 4143?4149 (2000).

    CAS  PubMed  Google Scholar 

  42. 42

    Sun, Z., Hsiao, J., Fay, D. S. & Stern, D. F. Rad53 FHA domain associated with phosphorylated Rad9 in the DNA damage checkpoint. Science 281, 272?274 (1998).The original report that identifies a role for the Rad53 FHA2 domain in phosphospecific interactions between Rad9 and Rad53.

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Li, J., Smith, G. P. & Walker, J. C. Kinase interaction domain of kinase-associated protein phosphatase, a phosphoprotein-binding domain. Proc. Natl Acad. Sci. USA 96, 7821?7826 (1999).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    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).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Durocher, D. et al. The molecular basis of FHA domain: phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms. Mol. Cell 6, 1169?1182 (2000).A detailed in vitro binding analysis, which shows that FHA domains have high affinity for phospho-threonine residues. The FHA optimal recognition motif was identified as pTXXD (in which T is threonine, D is aspartic acid and X is any amino acid).

    CAS  Article  PubMed  Google Scholar 

  46. 46

    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).Evidence for an essential role of the Chk2 FHA domain and autophosphorylation of threonines 383 and 387 in the Chk2 activation loop for the full activation of the kinase.

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Gilbert, C. S., Green, C. M. & Lowndes, N. F. Budding yeast Rad9 is an ATP-dependent Rad53 activating machine. Mol. Cell 8, 129?136 (2001).This study proposes an intriguing model of Rad53 activation whereby Mec1/Tel1-dependent phosphorylation of Rad9 converts the latter protein to a scaffold that brings two Rad53 molecules into close proximity.

    CAS  Article  PubMed  Google Scholar 

  48. 48

    Ward, I. M., Wu, X. & Chen, J. Threonine 68 of Chk2 is phosphorylated at sites of DNA strand breaks. J. Biol. Chem. (in the press).

  49. 49

    Bork, P. et al. A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins. FASEB J. 11, 68?76 (1997).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    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).

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Alcasabas, A. A. et al. Mrc1 transduces signals of DNA replication stress to activate Rad53. Nature Cell Biol. 3, 958?965 (2001).This study and reference 52 indicates that in yeast, Mrc1 might serve as a replicative counterpart of Rad9 and crb2 in activation of the Rad53 and cds1 kinases, respectively.

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Tanaka, K. & Russell, P. Mrc1 channels the DNA replication arrest signal to checkpoint kinase Cds1. Nature Cell Biol. 3, 966?972 (2001).

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Shieh, S. Y., Ahn, J., Tamai, K., Taya, Y. & Prives C. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 14, 289?300 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Chehab, N. H., Malikzay, A., Stavridi, E. S. & Halazonetis, T. D. Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc. Natl Acad. Sci. USA 96, 13777?13782 (1999).Phosphorylation of the serine 20 residue of p53 was shown to be required for its DNA-damage-dependent stabilization. This was soon followed by identification of Chk1 and Chk2 as the kinases that mediate this phosphorylation (references 53 and 55).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Chehab, N. H., Malikzay, A., Appel, M. & Halazonetis, T. D. Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev. 14, 278?288 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307?310 (2000).

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Ryan, K. M., Phillips, A. C. & Vousden, K. H. Regulation and function of the p53 tumor suppressor protein. Curr. Opin. Cell Biol. 13, 332?337 (2001).

    CAS  Article  PubMed  Google Scholar 

  58. 58

    Hirao, A. et al. DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287, 1824?1827 (2000).The first ? and, so far, the only ? report on Chk2 -knockout mouse embryo fibroblasts, which indicates an involvement of Chk2 in DNA-damage-dependent stabilization of p53 and G2/M checkpoint arrest.

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Lee, J. S., Collins, K. M., Brown, A. L., Lee, C. H. & Chung, J. H. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404, 201?204 (2000).The association with, and phosphorylation of, BRCA1 by Chk2 was identified as an important event in BRCA1-dependent DNA-damage checkpoint function.

    CAS  Article  PubMed  Google Scholar 

  60. 60

    Scully, R. & Livingston, D. M. In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature 408, 429?432 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Xu, B., Kim, S. & Kastan, M. B. Involvement of BRCA1 in S-phase and G(2)-phase checkpoints after ionizing irradiation. Mol. Cell. Biol. 21, 3445?3450 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Wang, Y. et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14, 927?939 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Sanchez, Y. et al. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science 277, 1497?1501 (1997).

    CAS  Article  PubMed  Google Scholar 

  64. 64

    Peng, C. Y. et al. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 277, 1501?1505 (1997).

    CAS  Article  PubMed  Google Scholar 

  65. 65

    Zeng, Y. & Piwnica-Worms, H. DNA damage and replication checkpoints in fission yeast require nuclear exclusion of the Cdc25 phosphatase via 14-3-3 binding. Mol. Cell. Biol. 19, 7410?7419 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    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  Article  PubMed  Google Scholar 

  67. 67

    Falck, J., Mailand, N., Syljuåsen, R. G., Bartek, J. & Lukas, J. The ATM?Chk2?Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410, 842?847 (2001).Identification of the Chk2-mediated degradation of the Cdc25A phosphatase as a rate-limiting step in the DNA damage intra-S-phase checkpoint in response to ionizing radiation.

    CAS  Article  PubMed  Google Scholar 

  68. 68

    Mailand, N. et al. Rapid destruction of human Cdc25A in response to DNA damage. Science 288, 1425?1429 (2000).This report and reference 69 shows a rapid, checkpoint-dependent degradation of Cdc25A in response to ultraviolet radiation and stalled replication, respectively.

    CAS  Article  PubMed  Google Scholar 

  69. 69

    Molinari, M., Mercurio, C., Dominguez, J., Goubin, F. & Draetta, G. F. Human Cdc25A inactivation in response to S phase inhibition and its role in preventing premature mitosis. EMBO Rep. 1, 71?79 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Petrini, J. H. The Mre11 complex and ATM: collaborating to navigate S phase. Curr. Opin. Cell Biol. 12, 293?296.

  71. 71

    Kastan, M. B. Cell cycle. Checking two steps. Nature 410, 766?767 (2001).

    CAS  Article  PubMed  Google Scholar 

  72. 72

    Banin, S. et al. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281, 1674?1677 (1998).

    CAS  Article  PubMed  Google Scholar 

  73. 73

    Canman, C. E. et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281, 1677?1679 (1998).

    CAS  Article  PubMed  Google Scholar 

  74. 74

    Maya, R. et al. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev. 15, 1067?1077 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Cortez, D., Wang, Y., Qin, J. & Elledge, S. J. Requirement of ATM-dependent phosphorylation of BRCA1 in the DNA damage response to double-strand breaks. Science 286, 1162?1166 (1999).

    CAS  Article  PubMed  Google Scholar 

  76. 76

    Tibbetts, R. S. et al. Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev. 14, 2989?3002 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Li, S. et al. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature 406, 210?215 (2000).

    CAS  Article  PubMed  Google Scholar 

  78. 78

    Barlow, C. et al. ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation. Proc. Natl Acad. Sci. USA 97, 871?876 (2000).

    CAS  Article  PubMed  Google Scholar 

  79. 79

    Lukas, C. et al. DNA damage-activated kinase Chk2 is independent of proliferation or differentiation yet correlates with tissue biology. Cancer Res. 61, 4990?4993 (2001).This study highlights the striking differences between human CHK2 and CHK1, and reports an unexpected correlation of CHK2 expression with tissue biology.

    CAS  PubMed  Google Scholar 

  80. 80

    Bartkova, J. et al. Chk2 tumour suppressor protein in human spermatogenesis and testicular germ-cell tumours. Oncogene 20, 5897?5902 (2001).

    CAS  Article  PubMed  Google Scholar 

  81. 81

    Flaggs, G. et al. ATM-dependent interactions of a mammalian chk1 homolog with meiotic chromosomes. Curr. Biol. 7, 977?986 (1997).

    CAS  Article  PubMed  Google Scholar 

  82. 82

    Kaneko, Y. et al. Cell cycle-dependent and ATM-independent expression of human Chk1 kinase. Oncogene 18, 3673?3681 (1999).

    CAS  Article  PubMed  Google Scholar 

  83. 83

    Bartek, J. & Lukas, J. Mammalian G1- and S-phase checkpoints in response to DNA damage. Curr. Opin. Cell Biol. (in the press).

  84. 84

    Bell, D. W. et al. Heterozygous germ line hCHK2 mutations in Li?Fraumeni syndrome. Science 286, 2528?2531 (1999).The identification of germline mutations in the CHK2 gene in Li?Fraumeni families with wild-type p53, which indicates a role for CHK2 as a tumour suppressor. Subsequently, identical and additional mutations were found in sporadic cancers of different origin (references 86?88).

    CAS  Article  PubMed  Google Scholar 

  85. 85

    Sodha, N. et al. Screening for hCHK2 mutations. Science 289, 359 (2000).

  86. 86

    Haruki, N. et al. Histological type-selective, tumor-predominant expression of a novel CHK1 isoform and infrequent in vivo somatic CHK2 mutation in small cell lung cancer. Cancer Res. 60, 4689?4692 (2000).

    CAS  PubMed  Google Scholar 

  87. 87

    Hofman, W.-K. et al. Mutation analysis of the DNA-damage checkpoint gene CHK2 in myelodysplastic syndromes and acute myeloid leukemias. Leuk. Res. 25, 333?338 (2001).

    Article  Google Scholar 

  88. 88

    Vahteristo, P. et al. p53, CHK2, and CHK1 genes in Finnish families with Li?Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 61, 5718?5722 (2001).

    CAS  PubMed  Google Scholar 

  89. 89

    Falck, J. et al. Functional impact of concomitant versus alternative defects in the Chk2-p53 tumour suppressor pathway. Oncogene 20, 5503?5510 (2001).Evidence that the concomitant mutation of p53 and CHK2 might provide a selective advantage to tumour cells.

    CAS  Article  PubMed  Google Scholar 

  90. 90

    Wu, X., Webster, S. R. & Chen, J. Characterization of tumor-associated Chk2 mutations. J. Biol. Chem. 276, 2971?2974 (2001).

    CAS  Article  PubMed  Google Scholar 

  91. 91

    Matsuoka, S. et al. Reduced expression and impaired kinase activity of a Chk2 mutant identified in human lung cancer. Cancer Res. 61, 5362?5365 (2001).

    CAS  PubMed  Google Scholar 

  92. 92

    Yao, S. L. et al. Selective radiosensitization of p53-deficient cells by caffeine-mediated activation of p34cdc2 kinase. Nature Med. 2, 1140?1143 (1996).

    CAS  Article  PubMed  Google Scholar 

  93. 93

    Suganuma, M., Kawabe, T., Hori, H., Funabiki, T. & Okamoto, T. Sensitization of cancer cells to DNA damage-induced cell death by specific cell cycle G2 checkpoint abrogation. Cancer Res. 59, 5887?5891 (1999).

    CAS  PubMed  Google Scholar 

  94. 94

    Nghiem, P., Park, P. K., Kim, Y. Vaziri, C. & Schreiber, S. L. ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation. Proc. Natl Acad. Sci. USA 98, 9092?9097 (2001).

    CAS  Article  PubMed  Google Scholar 

  95. 95

    Yu, L. et al. UCN-01 abrogates G2 arrest through a Cdc2-dependent pathway that is associated with inactivation of the Wee1Hu kinase and activation of the Cdc25C phosphatase. J. Biol. Chem. 273, 33455?33464 (1998).

    CAS  Article  PubMed  Google Scholar 

  96. 96

    Graves, P. R. et al. The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J. Biol. Chem. 275, 5600?5605 (2000).

    CAS  Article  PubMed  Google Scholar 

  97. 97

    Chen, M. S., Hurov, J., White, L. S., Woodford-Thomas, T. & Piwnica-Worms, H. Absence of apparent phenotype in mice lacking Cdc25C protein phosphatase. Mol. Cell. Biol. 21, 3853?3861 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Affiliations

Authors

Corresponding author

Correspondence to Jiri Bartek.

Related links

Related links

DATABASES

Interpro:

FHA

 LocusLink:

ATR

Bax

CtIP

cyclin E

GADD45

p21CIP1/WAF1

 OMIM:

ataxia-telangiectasia

ataxia-telangiectasia-like disorder

Nijmegen breakage syndrome

 Saccharomyces Genome Database:

Mec1

Mek1

Mrc1

Mre11

Rad3

Rad9

Rad50

Rad53

 Swiss-Prot:

53BP1

ATM

BRCA1

c-Abl

Cdc25A

Cdc25C

Chk1

Chk2

Mdm2

p53

Glossary

EPIGENETIC CHANGES

The alteration of gene expression through transcriptional (due to promoter methylation) or post-transcriptional mechanisms, rather than 'genetic' alteration of sequences of bases in genomic DNA.

RADIOMIMETIC DRUGS

Drugs that have cellular effects that are similar to those of ionizing radiation, such as the induction of double-stranded DNA breaks.

ACTIVATION LOOP

A conserved structural motif in kinase domains, which needs to be phosphorylated for full activation of the kinase.

SRC HOMOLOGY-3 (SH3) DOMAIN

A non-catalytic homology region which mediates protein?protein interactions and was first identified in Src-related protein kinases. SH3 domains bind to proline (Pro)-rich peptides that contain the minimal consensus Pro?X?X?Pro (in which X is any amino acid).

BRCA1

A checkpoint regulator and tumour suppressor, which is mutated with high incidence in human breast and ovarian cancers.

BRCT HOMOLOGY DOMAIN

An evolutionarily conserved protein?protein interaction domain, first described in the carboxy-terminal part of the BRCA1 tumour suppressor (BRCT; BRCA1 carboxy terminal), and subsequently identified in other checkpoint proteins.

HOMOLOGOUS RECOMBINATIONAL REPAIR

A mechanism for the repair of double-stranded DNA breaks, which relies on the presence of the homologous, intact DNA partner as a template.

TRANSCRIPTION-COUPLED REPAIR

Preferential removal of lesions from the DNA strands in genes that are actively transcribed by RNA polymerase II.

CHROMATIN REMODELLING

Dynamic changes of chromatin organization, which are required for optimal execution of processes such as DNA replication, gene transcription, DNA repair or chromosome segregation.

14-3-3 PROTEINS

An evolutionarily conserved group of regulatory proteins that bind to discrete phosphoserine-containing motifs. 14-3-3 proteins seem to sequester their binding partners and, in some cases, actively export them to the cytoplasm.

ORIGINS OF DNA REPLICATION

Sites on chromosomal DNA where replicative DNA synthesis is initiated. In some organisms, such as yeast, the origins of replication are defined by a specific DNA sequence.

SPERMATOGONIA AND SPERMATOCYTES

Successive developmental stages of male germ-cell maturation. Mitotically proliferating spermatogonia mature into spermatocytes, which undergo meiotic divisions, followed by functional maturation into spermatids and spermatozoa.

LI?FRAUMENI SYNDROME

A highly cancer-prone familial disorder (clinically defined by Li and Fraumeni in 1988), that is caused by germline mutations in TP53 or other tumour-suppressor genes, including CHK2.

E2F TRANSCRIPTION FACTORS

A family of six proteins that regulate expression of genes that are required for DNA replication.

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Bartek, J., Falck, J. & Lukas, J. Chk2 kinase — a busy messenger. Nat Rev Mol Cell Biol 2, 877–886 (2001). https://doi.org/10.1038/35103059

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