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Chapter 20 : Cell Cycle Checkpoints

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Abstract:

This chapter begins with a discussion on the signal transduction network that results in altered duration of the various well-defined stages of the eukaryotic cell cycle, now collectively referred to as checkpoints. However, it is clear that cell cycle arrest is only one aspect of a very multifaceted response that includes modification of repair proteins as well as their regulation at the transcriptional level. Following a brief historical introduction, this network is discussed as a signal transduction process, with sensors for DNA damage, mediators that amplify and convert a sensor input into a transmissible signal, amplifiers, transmitters, and downstream effectors. This chapter also integrates information from different organisms, using , , and human cells as the main systems, with an occasional glance at or . The avoidance of genetic instability is a major theme, and the many implications for understanding the phenotype of cancer cells are also discussed in this chapter.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20

Key Concept Ranking

DNA Synthesis
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Small Interfering RNA
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DNA Damage
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DNA Replication Inhibitors
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Figures

Image of Figure 20–1
Figure 20–1

Cdk activities drive cell cycle progression. (A) In this simplified view, Cdk association with different cyclins present during different stages of the cell cycle determines its activity and substrate specificity. Only one Cdk species and two cyclins specific for G and G (C and C, respectively) are depicted. (B) Scheme of the mammalian cell cycle showing the main Cdk activities (CDK4, CDK2, and CDK1) and the expression of their respective cyclin partners (cyclins D1, E, A, and B) as a function of the cell cycle stage. Reversible exit into a resting stage (G) is also indicated, as well as certain control elements of G/S progression—the transcription factors RB1, p53, and the Cdk inhibitor p21. These regulator proteins are discussed in detail in the text. (Panel B adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–2
Figure 20–2

Principles of Cdk regulation. Activity is positively regulated by association with the cyclin subunit and negatively regulated by association with Cki. Depicted are specific threonine or tyrosine residues whose phosphorylation can be activating or inhibiting. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–3
Figure 20–3

The basic observations of checkpoint arrest in budding yeast. (A and B) When irradiated with X rays, wild-type cells arrest as a large-budded cell in G/M, presumably to allow time for DNA repair before resuming cell cycle progression. (C) A repair-deficient mutant such as a mutant stays arrested in G/M and cannot resume cell division. (D) An arrest-deficient mutant such as a mutant does not arrest in G/M but continues cell cycle progression in the presence of unrepaired DNA damage, resulting in the formation of microcolonies of dead cells. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–4
Figure 20–4

Influence of inhibition of M phase on the X-ray sensitivity of Cells were synchronized in early M by incubation in the presence of the microtubule-destabilizing drug methyl benzimidazole-2-yl-carbamate (MBC), treated with X rays, and plated immediately (black lines) or after an additional 4 h of incubation in the presence of MBC (gold lines). By comparison with the wild-type strain (A), survival of colony-forming cells is significantly enhanced in the mutant strain defective in G/M arrest by imposition of such an artificial block after irradiation (B). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–5
Figure 20–5

Premitotic cell cycle arrest of in response to DNA damage (shown here as DSB) or unreplicated DNA is interpreted as a converging pathway with common steps (dependent on and and steps specific for damaged DNA (dependent on and (Adapted from references and .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–6
Figure 20–6

Defective UV radiation-induced G arrest in the mutant. Cells of a wild-type strain and an isogenic deletion mutant were synchronized in early G, treated with UV radiation at 0 or 30 J/m (— UV and + UV, respectively), and immediately released. Cell cycle progression was monitored as a function of time (0 to 70 min) by flow-cytometric analysis of DNA content (see Fig. 20–6 ). The left-hand peak in every panel corresponds to cells in G, and the right-hand peak corresponds to cells in G or M. Compared with the significant G arrest in wild-type cells, no arrest is observed in cells treated with UV radiation. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–7
Figure 20–7

The “cut” phenotype of UV radiation-treated (100 J/m) wild-type cells undergo checkpoint arrest. The cells elongate, but entry into mitosis is prevented. A checkpoint mutant the equivalent of shows septation in spite of an undivided nucleus, thus fragmenting nuclear DNA. (Courtesy of S. Mochida and M. Yanagida.)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–8
Figure 20–8

Multiparameter FACS analysis to determine cell cycle distributions within a cell population. Cells that have been pulse-labeled with BrdU are fixed, stained with propidium iodide and fluorescent antibody against BrdU, and subjected to analysis by flow cytometry. The cells are illuminated by a laser beam, and the emitted fluorescence is analyzed wavelength specifically. Signals are plotted according to propidium iodide ( axis) and BrdU fluorescence axis). The fraction of cells in S phase can be clearly distinguished from those in G and G/M. FITC, fluorescein isothiocyonate. (Adapted from references and .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–9
Figure 20–9

Microinjection of a linearized but not circular plas-mid into nuclei of fibroblasts can induce p53-dependent G arrest ( ). Circular plasmids with large single-stranded gaps are also active, but those with small gaps are not. nt, nucleotide.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–10
Figure 20–10

Phylogenetic tree and domain structure of PI3 kinase-related kinases. (A) Scheme of evolutionary relationships between members of the various protein subfamilies from selected species (Sp, Sc, Mm, Hs, Dm, (B) The HEAT repeat architecture of these proteins is shown. Common and ATM-, ATR-, and mTOR-specific HEAT units are depicted upstream of the C-terminal PI3 kinase domain (PI3K), defining certain subfamilies shown in panel A. (Adapted from references and .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–11
Figure 20–11

Model for activation of ATM kinase. Without cellular stress, nuclear ATM forms dimers that are catalytically inactive. Interaction of the so-called FAT domain with the kinase domain prevents ATM kinase from phosphorylating its targets. IR appears to alter some aspect of chromatin structure, and this signal activates ATM for intermolecular phosphorylation of Ser1981. The dimer is disrupted, and ATM can now phosphorylate its downstream targets, involved in cell cycle arrest, DNA repair, and apoptosis. As discussed in chapter 21, adaptor proteins may be required. ATM also phosphorylates H2AX at DSB sites and colocalizes in foci, the latter possibly involved in damage signal amplification and certain aspects of DNA repair. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–12
Figure 20–12

Model of the 9-1-1 complex. The Rad9-Rad1-Hus1 heterotrimer is a specialized version of the sliding-clamp processivity factor that loads onto damaged DNA. The model of the 91-1 complex shown here is based on the crystal structure of the PCNA homotrimeric sliding clamp (PDB accession code 1AXC).

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–13
Figure 20–13

Visualization of 9-1-1 complex loading by electron microscopy. Purified components were incubated with a 6.9-kb nicked plasmid. Loaded 9-1-1 complexes are indicated by arrows. The large aggregate presumably represents the 9-1-1 complex interacting with the RFC-RAD17Sp/Hs complex while being loaded. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–14
Figure 20–14

Ddc1-GFP focus formation correlates with the incidence of DNA damage in A single DSB was introduced by HO endonuclease expression (HO). DNA damage at chromosome ends results from temperature shift of a mutant, and more than one focus is visible Temperature-dependent inactivation of DNA ligase I results in multiple damaged sites WT, wild type. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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Image of Figure 20–15
Figure 20–15

Model for the initial steps of DNA damage recognition initiating checkpoint responses, exemplified with the human proteins. To be recognized by ATR-ATRIP, DSB may need to be resected and the exposed single strands are then bound by RPA (left). Independently, the RAD17-RFC complex loads the 9-1-1 complex at the single-stranded DNA/double-stranded DNA junction. Only in this configuration might ATR find its targets such as RAD17 or RAD9. The other PI3 kinase-like kinase, ATM, interacts with the MRN complex (right). Its NBS1 component is phosphorylated by ATM. It is possible that this complex enables ATM to select further targets, such as histone H2AX.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 753-777. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch20
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References

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1. Abraham, R. T., 2001. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 15:21772196.
2. Agarwal, M. L.,, A. Agarwal,, W. R. Taylor,, Z. Q. Wang,, E. F. Wagner, and, G. R. Stark. 1997. Defective induction but normal activation and function of p53 in mouse cells lacking poly-ADP-ribose polymerase. Oncogene 15:10351041.
3. Ahmed, S., and, J. Hodgkin. 2000. MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans. Nature 403:159164.
4. Al-Khodairy, F., and, A. M. Carr. 1992. DNA repair mutants defining G2 checkpoint pathways in Schizosaccharomyces pombe. EMBO J. 11:13431350.
5. Al-Khodairy, F.,, E. Fotou,, K. S. Sheldrick,, D. J. F. Griffiths,, A. R. Lehmann, and, A. M. Carr. 1994. Identification and characterization of new elements involved in checkpoint and feedback controls in fission yeast. Mol. Biol. Cell 5:147160.
6. Allen, J. B.,, Z. Zhou,, W. Siede,, E. C. Friedberg, and, S. J. Elledge. 1994. The SAD1/RAD53 protein kinase controls multiple checkpoints and DNA damage induced transcription in yeast. Genes Dev. 8:24012415.
7. Antoccia, A.,, M. Stumm,, K. Saar,, R. Ricordy,, P. Maraschio, and, C. Tanzarella. 1999. Impaired p53-mediated DNA damage response, cell-cycle disturbance and chromosome aberrations in Nijmegen breakage syndrome lymphoblastoid cell lines. Int. J. Radiat. Biol. 75:583591.
8. Araki, H.,, S.-H. Leem,, A. Phongdara, and, A. Sugino. 1995. Dpb11, which interacts with DNA polymerase II(e) in Saccharomyces cerevisiae, has a dual role in S-phase progression and at a cell cycle checkpoint. Proc. Natl. Acad. Sci. USA 92:1179111795.
9. Aravind, L.,, D. R. Walker, and, E. V. Koonin. 1999. Conserved domains in DNA repair proteins and evolution of repair systems. Nucleic Acids Res. 27:12231242.
10. Banin, A.,, L. Moyal,, S.-Y. Shieh,, Y. Taya,, C. W. Anderson,, L. Chessa,, N. I. Smorodinsky,, C. Prives,, Y. Reiss,, Y. Shiloh, and, Y. Ziv. 1998. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281:16741677.
11. Bao, S.,, X. Shen,, K. Shen,, Y. Liu, and, X.-F. Wang. 1998. The mammalian Rad24 homologous to yeast Saccharomyces cerevisiae Rad24 and Schizosaccharomyces pombe Rad17 is involved in DNA damage checkpoint. Cell Growth Differ. 9:961967.
12. Bao, S.,, R. S. Tibbetts,, K. M. Brumbaugh,, Y. Fang,, D. A. Richardson,, A. Ali,, S. M. Chen,, R. T. Abraham, and, X.-F. Wang. 2001. ATR/ATM- mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature 411:969974.
13. Barlow, C.,, K. D. Brown,, C.-X. Deng,, D. A. Tagle, and, A. Wyn-shaw-Boris. 1997. Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways. Nat. Genet. 17:453456.
14. Barlow, C.,, S. Hirotsune,, R. Paylor,, M. Liyanage,, M. Eckhaus,, F. Collins,, Y. Shiloh,, J. N. Crawley,, T. Ried,, D. Tagle, and, A. Wynshaw-Boris. 1996. Atm-deficient mice: a paradigm for ataxia telangiectasia. Cell 86:159171.
15. Barlow, C.,, M. Liyanage,, P. B. Moens,, M. Tarsounas,, K. Na-gashima,, K. Brown,, S. Rottinghaus,, S. P. Jackson,, D. Tagle,, T. Ried, and, A. Wynshaw-Boris. 1998. Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. Development 125:40074017.
16. Bartek, J.,, C. Lukas, and, J. Lukas. 2004. Checking on DNA damage in S phase. Nat. Rev. Mol. Cell Biol. 5:793804.
17. Bartek, J., and, J. Lukas. 2003. Damage alert. Nature 421:486488.
18. Beamish, H.,, R. Williams,, P. Chen, and, M. F. Lavin. 1996. Defect in multiple cell cycle checkpoints in ataxia-telangiectasia postirradiation. J. Biol. Chem. 271:2048620493.
19. Bermudez, V. P.,, L. A. Lindsey-Boltz,, A. J. Cesare,, Y. Maniwa,, J. D. Griffith,, J. Hurwitz, and, A. Sancar. 2003. Loading of the human 9–1-1 checkpoint complex onto DNA by the checkpoint clamp loader hRad17-replication factor C complex in vitro. Proc. Natl. Acad. Sci. USA 100:16331638.
20. Bessho, T., and, A. Sancar. 2000. Human DNA damage checkpoint protein hRAD9 is a 3’ to 5’ exonuclease. J. Biol. Chem. 275:74517454.
21. Blasina, A.,, B. D. Price,, G. A. Turenne, and, C. H. McGowan. 1999. Caffeine inhibits the checkpoint kinase ATM. Curr. Biol. 9:11351138.
22. Blaydes, J. P.,, A. L. Craig,, M. Wallace,, H. M. -L. Ball,, N. J. Traynor,, N. K. Gibbs, and, T. R. Hupp. 2000. Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways. Oncogene 19:38293839.
23. Brodsky, M. H.,, J. J. Sekelsky,, G. Tsang,, R. S. Hawley, and, G. M. Rubin. 2000. mus304 encodes a novel DNA damage checkpoint protein required during Drosophila development. Genes Dev. 14:666678.
24. Brown, E. J., and, D. Baltimore. 2000. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14:397402.
25. Brown, E. J., and, D. Baltimore., 2003. Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev. 17:615628.
26. Brown, K. D.,, A. Rathi,, R. Kamath,, D. I. Beardsley,, Q. Zhan,, J. Mannino, and, R. Baskaran. 2003. The mismatch repair system is required for S-phase checkpoint activation. Nat. Genet. 33:8084.
27. Buchmann, A.,, J. Skaar, and, J. DeCaprio. 2004. Activation of a DNA damage checkpoint response in a TAF1-defective cell line. Mol. Cell. Biol. 24:53325339.
28. Budzowska, M.,, I. Jaspers,, J. Essers,, H. de Waard,, E. van Drunen,, K. Hanada,, B. Beverloo,, R. W. Hendriks,, A. de Klein,, R. Kanaar,, J. H. Hoeijmakers, and, A. Maas. 2004. Mutation of the mouse Rad17 gene leads to embryonic lethality and reveals a role in DNA damage-dependent recombination. EMBO J. 23:35483558.
29. Burma, S.,, B. P. Chen,, M. Murphy,, A. Kurimasa, and, D. J. Chen. 2001. ATM phosphorylates histone H2AX in response to DNA double- strand breaks. J. Biol. Chem. 276:4246242467.
30. Burma, S.,, A. Kurimasa,, G. Xie,, Y. Taya,, R. Araki,, M. Abe,, H. A. Crissman,, H. Ouyang,, G. C. Li, and, D. J. Chen. 1999. DNA-dependent protein kinase-independent activation of p53 in response to DNA damage. J. Biol. Chem. 274:1713917143.
31. Burtelow, M. A.,, S. H. Kaufmann, and, L. M. Karnitz. 2000. Retention of the human Rad9 checkpoint complex in extraction-resistant nuclear complexes after DNA damage. J. Biol. Chem. 275:2634326348.
32. Burtelow, M. A.,, P. M. K. Roos-Mattjus,, M. Rauen,, J. R. Babendure, and, L. M. Karnitz. 2001. Reconstitution and molecular analysis of the hRad9-hHus1-hRad1 (9–1-1) DNA damage responsive checkpoint complex. J. Biol. Chem. 276:2590325909.
33. Buscemi, G.,, C. Savio,, L. Zannini,, F. Micciche,, D. Masnada,, M. Nakanishi,, H. Tauchi,, K. Komatsu,, S. Mizutani,, K. Khanna,, P. Chen,, P. Concannon,, L. Chessa, and, D. Delia. 2001. Chk2 activation dependence on Nbs1 after DNA damage. Mol. Cell. Biol. 21:52145222.
34. Caspari, T.,, M. Dahlen,, G. Kanter-Smoler,, H. D. Lindsay,, K. Hof-mann,, K. Papadimitriou,, P. Sunnerhagen, and, A. M. Carr. 2000. Characterization of Schizosaccharomyces pombe Hus1: a PCNA-related protein that associates with Rad1 and Rad9. Mol. Cell. Biol. 74:12541262.
35. Cejka, P.,, L. Stojic,, G. Marra, and, J. Jiricny. 2004. Is mismatch repair really required for ionizing radiation-induced DNA damage signaling? Nat. Genet. 36:432433.
36. Cejka, P.,, L. Stojic,, N. Mojas,, A. M. Russell,, K. Heinimann,, E. Cannavo,, M. di Pietro,, G. Marra, and, J. Jiricny. 2003. Methylation-induced G2/M arrest requires a full complement of the mismatch repair protein hMLH1. EMBO J. 22:22452254.
37. Chahwan, C.,, T. M. Nakamura,, S. Sivakumar,, P. Russell, and, N. Rhind. 2003. The fission yeast Rad32 (Mre11)-Rad50-Nbs1 complex is required for the S-phase DNA damage checkpoint. Mol. Cell. Biol. 23:65646573.
38. Chen, M.-J.,, Y.-T. Lin,, H. B. Lieberman,, G. Chen, and, E. Y. -H. P. Lee. 2001. ATM-dependent phosphorylation of human Rad9 is required for ionizing radiation-induced checkpoint activation. J. Biol. Chem. 276:1658016586.
39. Clarke, D. J.,, M. Segal,, G. Mondesert, and, S. I. Reed. 1999. The Pds1 anaphase inhibitor and Mec1 kinase define distinct checkpoints coupling S phase with mitosis in budding yeast. Curr. Biol. 9:365368.
40. Cliby, W. A.,, C. J. Roberts,, K. A. Cimprich,, C. M. Stringer,, J. R. Lamb,, S. L. Schreiber, and, S. H. Friend. 1998. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J. 17:159169.
41. Concannon, P., 2002. ATM heterozygosity and cancer risk. Nat. Genet. 32:8990.
42. Cooper, G., and, R. Hausman. 2004. The Cell: a Molecular Approach. ASM Press/Sinauer Associates, Washington, D.C., and Sunderland, Mass.
43. Cortez, D.,, S. Guntuku,, J. Qin, and, S. J. Elledge. 2001. ATR and ATRIP: partners in checkpoint signaling. Science 294:17131716.
44. Costanzo, V.,, T. Paull,, M. Gottesman, and, J. Gautier. 2004. Mre11 assembles linear DNA fragments into DNA damage signaling complexes. PLoSBiol. 2:06000609.
45. Culligan, K.,, A. Tissier, and, A. Britt. 2004. ATR regulates a G2-phase cell-cycle checkpoint in Arabidopsis thaliana. Plant Cell 16:10911104.
46. D’Amours, D., and, S. P. Jackson. 2002. The Mre11 complex: at the crossroads of DNA repair and checkpoint signalling. Nat. Rev. Mol. Cell Biol. 3:317327.
47. D’Amours, D., and, S. P. Jackson. 2001. The yeast Xrs2 complex functions in S phase checkpoint regulation. Genes Dev. 15:22382249.
48. Dart, D.,, K. Adams,, I. Akerman, and, N. Lakin. 2004. Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase. J. Biol. Chem. 279:1643316440.
49. Davis, T. W.,, C. Wilson-Van Patten,, M. Meyers,, K. A. Kunugi,, S. Cuthill,, C. Reznikoff,, C. Garces,, C. R. Boland,, T. J. Kinsella,, R. Fishel, and, D. A. Boothman. 1998. Defective expression of the DNA mismatch repair protein, MLH1, alters G2-M cell cycle checkpoint arrest following ionizing radiation. Cancer Res. 58:767778.
50. Dean, F. B.,, L. Lian, and, M. O’Donnell. 1998. cDNA cloning and gene mapping of human homologs for Schizosaccharomyces pombe rad17, rad1, and hus1 and cloning of homologs from mouse, Caenorhabditis elegans, and Drosophila melanogaster. Genomics 54:424436.
51. de Klein, A.,, M. Muijtjens,, R. van Os,, Y. Verhoeven,, B. Smit,, A. M. Carr,, A. R. Lehmann, and, J. H. J. Hoeijmakers. 2000. Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Curr. Biol. 10:479482.
52. Deming, P. B.,, C. A. Cistulli,, H. Zhao,, P. R. Graves,, H. Piwnica-Worms,, R. S. Paules,, C. S. Downes, and, W. K. Kaufmann. 2001. The human decatenation checkpoint. Proc. Natl. Acad. Sci. USA 98:1204412049.
53. Downes, C. S.,, D. J. Clarke,, A. M. Mullinger,, J. F. Gimenez-Abian,, A. M. Creighton, and, R. T. Johnson. 1994. A topoisomerase II-dependent G2 cycle checkpoint in mammalian cells. Nature 372:467470.
54. Dumaz, N.,, C. Drougard,, X. Quilliet,, M. Mezzina,, A. Sarasin, and, L. Daya-Grosjean. 1998. Recovery of the normal p53 response after UV treatment in DNA repair-deficient fibroblasts by retroviral-mediated correction with the XPD gene. Carcinogenesis 19:17011704.
55. Edwards, R. J.,, N. J. Bentley, and, A. M. Carr. 1999. A Rad3-Rad26 complex responds to DNA damage independently of other checkpoint proteins. Nat. Cell Biol. 1:393398.
56. Eller, M. S.,, T. Maeda,, C. Magnoni,, D. Atwal, and, B. A. Gilchrest. 1997. Enhancement of DNA repair in human skin cells by thymidine di-nucleotides: evidence for a p53-mediated mammalian SOS response. Proc. Natl. Acad. Sci. USA 94:1262712632.
57. Enoch, T.,, A. M. Carr, and, P. Nurse. 1992. Fission yeast genes involved in coupling mitosis to completion of DNA replication. Genes Dev. 6:20352046.
58. Faber, G., and, J. Kiefer. 1976. Budding and division delay in diploid yeast after irradiation, p., 264270. In J. Kiefer (ed.), Radiation and Cellular Control Processes. Springer Verlag KG, Berlin, Germany.
59. Franchitto, A.,, P. Pichierri,, R. Piergentili,, M. Crescenzi,, M. Big-nami, and, F. Palitti. 2003. The mammalian mismatch repair protein MSH2 is required for correct MRE11 and RAD51 relocalization and for efficient cell cycle arrest induced by ionizing radiation in G2 phase. Oncogene 22:21102120.
60. Frei, C., and, S. M. Gasser. 2000. RecQ-like helicases: the DNA replication checkpoint connection. J. Cell Sci. 113:26412646.
61. Frei, C., and, S. M. Gasser. 2000. The yeast Sgs1p helicase acts upstream of Rad53p in the DNA replication checkpoint and colocalizes with Rad53p in S-phase-specific loci. Genes Dev. 14:8196.
62. Freire, R.,, J. R. Murguía,, M. Tarsounas,, N. F. Lowndes,, P. B. Moens, and, S. P. Jackson. 1998. Human and mouse homologs of Schizosaccharomyces pombe radl+ and Saccharomyces cerevisiae RAD17: linkage to checkpoint control and mammalian meiosis. Genes Dev. 12:25602573.
63. Garg, R.,, S. Callens,, D. S. Lim,, C. E. Canman,, M. B. Kastan, and, B. Xu. 2004. Chromatin association of Rad17 is required for an ataxia telangiectasia and Rad-related kinase-mediated S-phase checkpoint in response to low-dose ultraviolet radiation. Mol. Cancer Res. 2:362369.
64. Garvik, B.,, M. Carson, and, L. Hartwell. 1995. Single-stranded DNA arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint. Mol. Cell. Biol. 15:61286138.
65. Giannattasio, M.,, F. Lazzaro,, M. P. Longhese,, P. Plevani, and, M. Muzi-Falconi. 2004. Physical and functional interactions between nucleotide excision repair and DNA damage checkpoint. EMBO J. 23:429438.
66. Giannattasio, M.,, F. Lazzaro,, E. Nunes,, W. Siede,, P. Plevani, and, M. Muzi-Falconi. 2004. DNA decay and limited Rad53 activation after liquid holding of UV-treated nucleotide excision repair deficient cells. DNA Repair 3:15911599.
67. Givan, A. L., 1992. Flow Cytometry: First Principles. Wiley-Liss, New York, N.Y.
68. Goukassian, D. A.,, E. Helms,, H. van Steeg,, C. van Oostrom,, J. Bhawan, and, B. A. Gilchrest. 2004. Topical DNA oligonucleotide therapy reduces UV-induced mutations and photocarcinogenesis in hairless mice. Proc. Natl. Acad. Sci. USA 101:39333938.
69. Grandin, N.,, C. Damon, and, M. Charbonneau. 2001. Cdc13 prevents telomere uncapping and Rad50-dependent homologous recombination. EMBO J. 20:61276139.
70. Green, C. M.,, H. Erdjument-Bromage,, P. Tempst, and, N. F. Lown-des. 2000. A novel Rad24 checkpoint protein complex closely related to replication factor C. Curr. Biol. 10:3942.
71. Greenwell, P. W.,, S. L. Kronmal,, S. E. Porter,, J. Gassenhuber,, B. Obermaier, and, T. D. Petes. 1995. TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell 82:823829.
72. Grenon, M.,, C. Gilbert, and, N. F. Lowndes. 2001. Checkpoint activation in response to double-strand breaks requires the Mre11/Rad50/Xrs2 complex. Nat. Cell Biol. 3:844847.
73. Griffith, J. D.,, L. A. Lindsey-Boltz, and, A. Sancar. 2002. Structures of the human Rad17-replication factor C and checkpoint Rad 9–1-1 complexes visualized by spray/low voltage microscopy. J. Biol. Chem. 277:1523315236.
74. Griffiths, D. J. F.,, N. C. Barbet,, S. McCready,, A. R. Lehmann, and, A. M. Carr. 1995. Fission yeast rad17: a homologue of budding yeast RAD24 that shares regions of sequence similarity with DNA polymerase accessory proteins. EMBO J. 14:58125823.
75. Grushcow, J. M.,, T. M. Holzen,, K. J. Park,, T. Weinert,, M. Lichten, and, D. K. Bishop. 1999. Saccharomyces cerevisiae checkpoint genes MEC1, RAD17 and RAD24 are required for normal meiotic recombination partner choice. Genetics 153:607620.
76. Guo, Z., and, W. G. Dunphy. 2000. Response of Xenopus Cds1 in cell-free extracts to DNA templates with double-stranded ends. Mol. Biol. Cell 11:15351546.
77. Gurley, K. E., and, C. J. Kemp. 1996. p53 induction, cell cycle checkpoints, and apoptosis in DNAPK-deficient scid mice. Carcinogenesis 17:25372542.
78. Hall, E., 2000. Radiobiology for the Radiologist, 5th ed. Lippincott Williams & Wilkins, Philadelphia, Pa.
79. Hall-Jackson, C. A.,, D. A. E. Cross,, N. Morrice, and, C. Smythe. 1999. ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK. Oncogene 18:67076713.
80. Hang, H., and, H. B. Lieberman. 2000. Physical interactions among human checkpoint control proteins HUS1p, RAD1p, and RAD9p, and implications for the regulation of cell cycle progression. Genomics 65:2433.
81. Hang, H.,, Y. Zhang,, R. L. Dunbrack, Jr.,, C. Wang, and, H. B. Lieberman. 2002. Identification and characterization of a paralog of human cell cycle checkpoint gene HUS1. Genomics 79:487492.
82. Hari, K. L.,, A. Santerre,, J. J. Sekelsky,, K. S. McKim,, J. B. Boyd, and, R. S. Hawley. 1995. The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene. Cell 82:815821.
83. Harper, J. W., and, S. J. Elledge. 1996. Cdk inhibitors in development and cancer. Curr. Opin. Genet. Dev. 6:5664.
84. Hartwell, L., 1992. Defects in a cell cycle checkpoint may be responsible for the genetic instability of cancer cells. Cell 71:543546.
85. Hartwell, L. H., and, M. B. Kastan. 1994. Cell cycle control and cancer. Science 266:18211828.
86. Heffernan, T. P.,, D. A. Simpson,, A. R. Frank,, A. N. Heinloth,, R. S. Paules,, M. Cordeiro-Stone, and, W. K. Kaufmann. 2002. An ATR-and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage. Mol. Cell. Biol. 22:85528561.
87. Heitzeberg, F.,, I. P. Chen,, F. Hartung,, N. Orel,, K. J. Angelis, and, H. Puchta. 2004. The Rad17 homologue of Arabidopsis is involved in the regulation of DNA damage repair and homologous recombination. Plant J. 38:954968.
88. Hekmat-Nejad, M.,, Z. You,, M. Yee,, J. W. Newport, and, K. A. Cim-prich. 2000. Xenopus ATR is a replication-dependent chromatin-binding protein required for the DNA replication checkpoint. Curr. Biol. 10:15651573.
89. Hofmann, E. R.,, S. Milstein,, S. J. Boulton,, M. Ye,, J. J. Hofmann,, L. Stergiou,, A. Gartner,, M. Vidal, and, M. O. Hengartner. 2002. Caenorhabditis elegans HUS-1 is a DNA damage checkpoint protein required for genome stability and EGL-1-mediated apoptosis. Curr. Biol. 12:19081918.
90. Hong, E. J., and, G. S. Roeder. 2002. A role for Ddc1 in signaling meiotic double-strand breaks at the pachytene checkpoint. Genes Dev. 16:363376.
91. Hopkins, K. M.,, W. Auerbach,, X. Y. Wang,, M. P. Hande,, H. Hang,, D. J. Wolgemuth,, A. L. Joyner, and, H. B. Lieberman. 2004. Deletion of mouse rad9 causes abnormal cellular responses to DNA damage, genomic instability, and embryonic lethality. Mol. Cell. Biol. 24:72357248.
92. Huang, L.-C.,, K. C. Clarkin, and, G. M. Wahl. 1996. p53-dependent cell cycle arrests are preserved in DNA-activated protein kinase-deficient mouse fibroblasts. Cancer Res. 56:29402944.
93. Huang, L.-C.,, K. C. Clarkin, and, G. M. Wahl. 1996. Sensitivity and selectivity of the DNA damage sensor responsible for activating p53- dependent G1 arrest. Proc. Natl. Acad. Sci. USA 93:48274832.
94. Ira, G.,, A. Pellicioli,, A. Balijja,, X. Wang,, S. Fiorani,, W. Carotenuto,, G. Liberi,, D. Bressan,, L. Wan,, N. M. Hollingsworth,, J. E. Haber, and, M. Foiani. 2004. DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431:10111017.
95. Jhappan, C.,, T. M. Yusufzai,, S. Anderson,, M. R. Anver, and, G. Merlino. 2000. The p53 response to DNA damage in vivo is independent of DNA-dependent protein kinase. Mol. Cell. Biol. 20:40754083.
96. Jiang, Y. W., and, C. M. Kang. 2003. Induction of S. cerevisiae filamentous differentiation by slowed DNA synthesis involves Mec1, Rad53 and Swe1 checkpoint proteins. Mol. Biol. Cell 14:51165124.
97. Jimenez, G. S.,, F. Bryntesson,, M. I. Torres-Arzayus,, A. Priestley,, M. Beeche,, S. Saito,, K. Sakaguchi,, E. Appella,, P. A. Jeggo,, G. E. Tacci-oli,, G. M. Wahl, and, M. Hubank. 1999. DNA-dependent protein kinase is not required for the p53-dependent response to DNA damage. Nature 400:8185.
98. Johnston, L. H., 1983. The cdc9 ligase joins completed replicons in baker’s yeast. Mol. Gen. Genet. 190:315317.
99. Jongmans, W.,, M. Vuillaume,, K. Chrzanowska,, D. Smeets,, K. Sperling, and, J. Hall. 1997. Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation. Mol. Cell. Biol. 17:50165022.
100. Kai, M.,, H. Tanaka, and, T. S.-F. Wang. 2001. Fission yeast Rad17 associates with chromatin in response to aberrant genomic structures. Mol. Cell. Biol. 21:32893301.
101. Kastan, M. B., and, D.-S. Lim. 2000. The many substrates and functions of ATM. Nat. Rev. Mol. Cell Biol. 1:179186.
102. Kastan, M. B.,, O. Onyekwere,, D. Sidransky,, B. Vogelstein, and, R. W. Craig. 1991. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51:63046311.
103. Kastan, M. B.,, Q. Zhan,, W. S. El-Deiry,, F. Carrier,, T. Jacks,, W. V. Walsh,, B. S. Plunkett,, B. Vogelstein, and, A. J. Fornace, Jr., 1992. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectesia. Cell 71:587597.
104. Kato, R., and, H. Ogawa. 1994. An essential gene, ESR1, is required for mitotic cell growth, DNA repair and meiotic recombination in Saccharomyces cerevisiae. Nucleic Acids Res. 22:31043112.
105. Kaur, R.,, C. F. Kostrub, and, T. Enoch. 2001. Structure-function analysis of fission yeast Hus1-Rad1-Rad9 checkpoint complex. Mol. Biol. Cell 12:37443758.
106. Kobayashi, M.,, A. Hirano,, T. Kumano,, S. L. Xiang,, K. Mihara,, Y. Haseda,, O. Matsui,, H. Shimizu, and, K. Yamamoto. 2004. Critical role for chicken Rad17 and Rad9 in the cellular response to DNA damage and stalled DNA replication. Genes Cells 9:291303.
107. Komatsu, K.,, W. Wharton,, H. Hang,, C. Wu,, S. Singh,, H. Lieber-man,, W. J. Pledger, and, H.-G. Wang. 2000. PCNA interacts with hHus1/ hRad9 in response to DNA damage and replication inhibition. Oncogene 19: 52915297.
108. Kondo, T.,, K. Matsumoto, and, K. Sugimoto. 1999. Role of a complex containing Rad17, Mec3, and Ddc1 in the yeast DNA damage checkpoint pathway. Mol. Cell. Biol. 19:11361143.
109. Kondo, T.,, T. Wakayama,, T. Naiki,, K. Matsumoto, and, K. Sug-imoto. 2001. Recruitment of Mec1 and Ddc1 checkpoint proteins to double-strand breaks through distinct mechanisms. Science 294:867870.
110. Kornbluth, S.,, C. Smythe, and, J. W. Newport. 1992. In vitro cell cycle arrest induced by using artificial DNA templates. Mol. Cell. Biol. 12: 32163223.
111. Kostrub, C. F.,, F. Al-Khodairy,, H. Ghazizadeh,, A. M. Carr, and, T. Enoch. 1997. Molecular analysis of hus1+, a fission yeast gene required for S-M and DNA damage checkpoints. Mol. Gen. Genet. 254:389399.
112. Kostrub, C. F.,, K. Knudsen,, S. Subramani, and, T. Enoch. 1998. Hus1p, a conserved fission yeast checkpoint protein, interacts with Rad1p and is phosphorylated in response to DNA damage. EMBO J. 17:20552066.
113. Kuerbitz, S. J.,, B. S. Plunkett,, W. V. Walsh, and, M. B. Kastan. 1992. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc. Natl. Acad. Sci. USA 89:74917495.
114. Kurz, E., and, S. Lees-Miller. 2004. DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA Repair 3:889900.
115. Lee, J.-H., and, T. T. Paull. 2004. Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 304:9396.
116. Lee, S. E.,, J. K. Moore,, A. Holmes,, K. Umezu,, R. D. Kolodner, and, J. E. Haber. 1998. Saccharomyces Ku70, Mre11/Rad50, and RPA proteins regulate adaptation to G2/M arrest after DNA damage. Cell 94:399409.
117. Levin, N.,, M.-A. Bjornsti, and, G. R. Fink. 1993. A novel mutation in DNA topoisomerase I of yeast causes DNA damage and RAD9-dependent cell cycle arrest. Genetics 133:799814.
118. Lieberman, H. B. (ed.)., 2003. Cell Cycle Checkpoint Protocols. Humana Press, Totowa, N.J.
119. Lieberman, H. B.,, K. M. Hopkins,, M. Nass,, D. Demetrick, and, S. Davey. 1996. A human homolog of the Schizosaccharomyces pombe rad9* checkpoint control gene. Proc. Natl. Acad. Sci. USA 93:1389013895.
120. Lim, D.-S.,, S.-T. Kim,, B. Xu,, R. S. Maser,, J. Lin,, J. H. J. Petrini, and, M. B. Kastan. 2000. ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature 404:613617.
121. Lindsey-Boltz, L. A.,, V. P. Bermudez,, J. Hurwitz, and, A. Sancar. 2001. Purification and characterization of human DNA damage checkpoint Rad complexes. Proc. Natl. Acad. Sci. USA 98:1123611241.
122. Lindsey-Boltz, L. A.,, E. M. Wauson,, L. M. Graves, and, A. San-car. 2004. The human Rad9 checkpoint protein stimulates the carbamoyl phosphate synthetase activity of the multifunctional protein CAD. Nucleic Acids Res. 32:45244530.
123. Ljungman, M., and, D. P. Lane. 2004. Transcription-guarding the genome by sensing DNA damage. Nat. Rev. Cancer 4:727737.
124. Loeb, L. A., 2001. A mutator phenotype in cancer. Cancer Res. 61:32303239.
125. Longhese, M. P.,, M. Clerici, and, G. Lucchini. 2003. The S-phase checkpoint and its regulation in Saccharomyces cerevisiae. Mutat. Res. 532: 4158.
126. Longhese, M. P., and, M. Foiani. Responses to replication of DNA damage. In W. Siede,, Y. W. Kow, and, P. W. Doetsch (ed.), DNA Damage Recognition, in press. Taylor & Francis, New York, N.Y.
127. Longhese, M. P.,, H. Neecke,, V. Paciotti,, G. Lucchini, and, P. Plevani. 1996. The 70 kDa subunit of replication protein A is required for the G1/S and intra-S DNA damage checkpoints in budding yeast. Nucleic Acids Res. 24:35333537.
128. Longhese, M. P.,, V. Paciotti,, R. Fraschini,, R. Zaccarini,, P. Plevani, and, G. Lucchini. 1997. The novel DNA damage checkpoint protein Ddc1p is phosphorylated periodically during the cell cycle and in response to DNA damage in budding yeast. EMBO J. 16:52165226.
129. Longhese, M. P.,, P. Plevani, and, G. Lucchini. 1994. Replication factor A is required in vivo for DNA replication repair, and recombination. Mol. Cell. Biol. 14:78847890.
130. Luo, Y.,, F. T. Lin, and, W. C. Lin. 2004. ATM-mediated stabilization of hMutL DNA mismatch repair proteins augments p53 activation during DNA damage. Mol. Cell. Biol. 24:64306444.
131. Lydall, D.,, Y. Nikolsky,, D. K. Bishop, and, T. Weinert. 1996. A meiotic recombination checkpoint controlled by mitotic checkpoint genes. Nature 383:840843.
132. Lydall, D., and, T. Weinert. 1995. Yeast checkpoint genes in DNA damage processing: implications for repair and arrest. Science 270:14881491.
133. Majka, J., and, P. M. Burgers. 2003. Yeast Rad17/Mec3/Ddc1: a sliding clamp for the DNA damage checkpoint. Proc. Natl. Acad. Sci. USA 100: 22492254.
134. Majka, J.,, B. Y. Chung, and, P. M. Burgers. 2004. Requirement for ATP by the DNA damage checkpoint clamp loader. J. Biol. Chem. 279: 2092120926.
135. Makiniemi, M.,, T. Hillukkala,, J. Tuusa,, K. Reini,, M. Vaara,, D. Huang,, H. Pospiech,, I. Majuri,, T. Westerling,, T.P. Makela, and, J. E. Syvaoja., 2001. BRCT domain-containing protein TopBP1 functions in DNA replication and damage response. J. Biol. Chem. 276:3039930406.
136. Marini, F.,, A. Pellicioli,, V. Paciotti,, G. Lucchini,, P. Plevani,, D. F. Stern, and, M. Foiani. 1997. A role for DNA primase in coupling DNA replication to DNA damage response. EMBO J. 16:639650.
137. Marquez, N.,, S. C. Chappell,, O. J. Sansom,, A. R. Clarke,, J. Court,, R. J. Errington, and, P. J. Smith. 2003. Single cell tracking reveals that Msh2 is a key component of an early-acting DNA damage-activated G2 checkpoint. Oncogene 22:76427648.
138. Melo, J. A.,, J. Cohen, and, D. P. Toczyski. 2001. Two checkpoint complexes are independently recruited to sites of DNA damage in vivo. Genes Dev. 15:28092821.
139. Meyn, M. S., 1995. Ataxia-telangiectasia and cellular responses to DNA damage. Cancer Res. 55:59916001.
140. Morrow, D. M.,, D. A. Tagle,, Y. Shiloh,, F. S. Collins, and, P. Hieter. 1995. TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1. Cell 82:831840.
141. Mossi, R., and, U. Hubscher. 1998. Clamping down on clamp loaders: the eukaryotic replication factor C. Eur. J. Biochem. 254:209216.
142. Murray, A., and, T. Hunt. 1993. The Cell Cycle: an Introduction. W. H. Freeman Co., New York, N.Y.
143. Murray, J. M.,, A. M. Carr,, A. R. Lehmann, and, F. Z. Watts. 1991. Cloning and characterization of the rad9 DNA repair gene from Schizosaccharomyces pombe. Nucleic Acids Res. 19:35253531.
144. Myung, K.,, C. Chen, and, R. Kolodner. 2001. Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae. Nature 411:10731076.
145. Nagasawa, H.,, K. H. Kraemer,, Y. Shiloh, and, J. B. Little. 1987. Detection of ataxia telangiectasia heterozygous cell lines by postirradiation cumulative labeling index: measurements with coded samples. Cancer Res. 47:398402.
146. Naiki, T.,, T. Kondo,, D. Nakada,, K. Matsumoto, and, K. Sugimoto. 2001. Chl12 (Ctf18) forms a novel replication factor C-related complex and functions redundantly with Rad24 in the DNA replication checkpoint pathway. Mol. Cell. Biol. 21:58385845.
147. Nakada, D.,, Y. Hirano, and, K. Sugimoto. 2004. Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway. Mol. Cell. Biol. 24:1001610025.
148. Nakada, D.,, T. Shimomura,, K. Matsumoto, and, K. Sugimoto. 2003. The ATM-related Tel1 protein of Saccharomyces cerevisiae controls a checkpoint response following phleomycin treatment. Nucleic Acids Res. 31:17151724.
149. Naureckiene, S., and, W. K. Holloman. 1999. DNA hydrolytic activity associated with the Ustilago maydis REC1 gene product analyzed in hairpin oligonucleotide substrates. Biochemistry 38:1437914386.
150. Navas, T. A.,, Z. Zhou, and, S. J. Elledge. 1995. DNA polymerase ε links the DNA replication machinery to the S phase checkpoint. Cell 80: 2939.
151. Neecke, H.,, G. Lucchini, and, M. P. Longhese. 1999. Cell cycle progression in the presence of irreparable DNA damage is controlled by a Mec1- and Rad53-dependent checkpoint in budding yeast. EMBO J. 18:44854497.
152. Nelson, D. M.,, X. Ye,, C. Hall,, H. Santos,, T. Ma,, G. D. Kao,, T. J. Yen,, J. W. Harper, and, P. D. Adams. 2002. Coupling of DNA synthesis and histone synthesis in S phase independent of cyclin/cdk2 activity. Mol. Cell. Biol. 22:74597472.
153. Nelson, W. G., and, M. B. Kastan. 1994. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol. Cell. Biol. 14:18151823.
154. Nigg, E. A., 2001. Mitotic kinases as regulators of cell division and its checkpoints. Nat. Rev. Mol. Cell Biol. 2:2132.
155. Nugent, C. I.,, T. R. Hughes,, N. F. Lue, and, V. Lundblad. 1996. Cdc13p: a single-strand telomeric DNA-binding protein with a dual role in yeast telomere maintenance. Science 274:249252.
156. Nur, E.,, A. Kamal,, T. K. Li,, A. Zhang,, H. Qi,, E. S. Hars, and, L. F. Liu. 2003. Single-stranded DNA induces ataxia telangiectasia mutant (ATM)/p53-dependent DNA damage and apoptotic signals. J. Biol. Chem. 278:1247512481.
157. Nurse, P., 1990. Universal control mechanism regulating onset of M-phase. Nature 344:503507.
158. Nyberg, K. A.,, R. J. Michelson,, C. W. Putnam, and, T. A. Wein-ert. 2002. Toward maintaining the genome: DNA damage and replication checkpoints. Annu. Rev. Genet. 36:617656.
159. O’Driscoll, M.,, V. L. Ruiz-Perez,, C. G. Woods,, P. A. Jeggo, and, J. A. Goodship. 2003. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat. Genet. 33:497501.
160. Orren, D. K.,, L. N. Petersen, and, V. A. Bohr. 1995. A UV- responsive G2 checkpoint in rodent cells. Mol. Cell. Biol. 15:37223730.
161. Osborn, A. J.,, S. J. Elledge, and, L. Zou. 2002. Checking on the fork: the DNA-replication stress-response pathway. Trends Cell Biol. 12:509516.
162. Paciotti, V.,, M. Clerici,, G. Lucchini, and, M. P. Longhese. 2000. The checkpoint protein Ddc2, functionally related to S. pombe Rad26, interacts with Mec1 and is regulated by Mec1-dependent phosphorylation in budding yeast. Genes Dev. 14:20462059.
163. Paciotti, V.,, G. Lucchini,, P. Plevani, and, M. P. Longhese. 1998. Mec1p is essential for phosphorylation of the yeast DNA damage checkpoint protein Ddc1p, which physically interacts with Mec3p. EMBO J. 17:41994209.
164. Painter, R. B., 1986. Inhibition of mammalian cell DNA synthesis by ionizing radiation. Int. J. Radiat. Biol. 49:771781.
165. Painter, R. B., and, B. R. Young. 1980. Radiosensitivity in ataxia telangiectasia: a new explanation. Proc. Natl. Acad. Sci. USA 77:73157317.
166. Parker, A. E.,, I. Van de Weyer,, M. C. Laus,, I. Oostveen,, J. Yon,, P. Verhasselt, and, W. H. M. L. Luyten. 1998. A human homologue of the Schizosaccharomyces pombe rad1 + checkpoint gene encodes an exonuclease. J. Biol. Chem. 273:1833218339.
167. Paulovich, A. G., and, L. H. Hartwell. 1995. A checkpoint regulates the rate of progression through S phase in S. cerevisiae in response to DNA damage. Cell 82:841847.
168. Paulovich, A. G.,, R. U. Margulies,, B. M. Garvik, and, L. H. Hart-well. 1997. RAD9, RAD17, and RAD24 are required for S phase regulation in Saccharomyces cerevisiae in response to DNA damage. Genetics 145:4562.
169. Perkins, E. J.,, A. Nair,, D. O. Cowley,, T. Van Dyke,, Y. Chang, and, D. A. Ramsden. 2002. Sensing of intermediates in V(D)Jrecombination by ATM. Genes Dev. 16:159164.
170. Perry, J., and, N. Kleckner. 2003. The ATRs, ATMs, and TORs are giant HEAT repeat proteins. Cell 112:151155.
171. Peters, J.-M., 1998. SCF and APC: the Yin and Yang of cell cycle regulated proteolysis. Curr. Biol. 10:759768.
172. Post, S. M.,, A. E. Tomkinson, and, E. Y. Lee. 2003. The human checkpoint Rad protein Rad17 is chromatin-associated throughout the cell cycle, localizes to DNA replication sites, and interacts with DNA polymerase e. Nucleic Acids Res. 31:55685575.
173. Proud, C. G., 2002. Regulation of mammalian translation factors by nutrients. Eur. J. Biochem. 269:53385349.
174. Rao, P. N., and, R. T. Johnson. 1970. Mammalian cell fusion studies on the regulation of DNA synthesis and mitosis. Nature 225:159164.
175. Rathmell, W. K.,, W. K. Kaufmann,, J. C. Hurt,, L. L. Byrd, and, G. Chu. 1997. DNA-dependent protein kinase is not required for accumulation of p53 or cell cycle arrest after DNA damage. Cancer Res. 57:6874.
176. Rauen, M.,, M. A. Burtelow,, V. M. Dufault, and, L. M. Karnitz. 2000. The human checkpoint protein hRad17 interacts with the PCNA-like proteins hRad1, hHus1, and hRad9. J. Biol. Chem. 275:2976729771.
177. Reed, S. I., 2003. Ratchets and clocks: the cell cycle, ubiquitylation and protein turnover. Nat. Rev. Mol. Cell Biol. 4:855864.
178. Roberts, J. M., 1999. Evolving ideas about cyclins. Cell 98:129132.
179. Roos-Mattjus, P.,, K. M. Hopkins,, A. J. Oestreich,, B. T. Vroman,, K. L. Johnson,, S. Naylor,, H. B. Lieberman, and, L. M. Karnitz. 2003. Phosphorylation of human Rad9 is required for genotoxin-activated checkpoint signaling. J. Biol. Chem. 278:2442824437.
180. Rotman, G., and, Y. Shiloh. 2000. ATM: a mediator of multiple responses to genotoxic stress. Oncogene 18:61356144.
181. Rouse, J., and, S. P. Jackson. 2000. LCD1 : an essential gene involved in checkpoint control and regulation of the MEC1 signalling pathway in Saccharomyces cerevisiae. EMBO J. 19:58015812.
182. Rouse, J., and, S. P. Jackson. 2002. Lcd1p recruits Mec1p to DNA lesions in vitro and in vivo. Mol. Cell 9:857869.
183. Rudolph, N. S., and, S. A. Latt. 1989. Flow cytometric analysis of X-ray sensitivity in ataxia telangiectasia. Mutat. Res. 211:3141.
184. Sarkaria, J. N.,, R. S. Tibbetts,, E. C. Busby,, A. P. Kennedy,, D. E. Hill, and, R. T. Abraham. 1998. Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res. 58:43754382.
185. Savitsky, K.,, A. Bar-Shira,, S. Gilad,, G. Rotman,, Y. Ziv,, L. Vana-gaite,, D. A. Tagle,, S. Smith,, T. Uziel,, S. Sfez,, M. Ashkenazi,, I. Pecker,, M. Frydman,, R. Harnik,, S. R. Patanjali,, A. Simmons,, G. A. Clines,, A. Sar-tiel,, R. A. Gatti,, L. Chessa,, O. Sanal,, M. F. Lavin,, N. G. J. Jaspers,, A. M. R. Taylor,, C. F. Arlett,, T. Miki,, S. M. Weissman,, M. Lovett,, F. S. Collins, and, Y. Shiloh. 1995. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268:17491753.
186. Savitsky, K.,, S. Sfez,, D. A. Tagle,, Y. Ziv,, A. Sartiel,, F. S. Collins,, Y. Shiloh, and, G. Rotman. 1995. The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Hum. Mol. Genet. 4:20252032.
187. Sherr, C. J., and, J. M. Roberts. 1999. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13:15011512.
188. Shiloh, Y., 1997. Ataxia telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu. Rev. Genet. 31:635662.
189. Shiloh, Y., 2001. ATM and ATR: networking cellular responses to DNA damage. Curr. Opin. Genet. Dev. 11:7177.
190. Shiloh, Y., 2003. ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3:155168.
191. Shiloh, Y., and, M. B. Kastan. 2001. ATM: Genome stability, neuronal development, and cancer cross paths. Adv. Cancer Res. 83:209254.
192. Shimada, K.,, P. Pasero, and, S. M. Gasser. 2002. ORC and the intra-S-phase checkpoint: a threshold regulates Rad53p activation in S phase. Genes Dev. 16:32363252.
193. Shimomura, T.,, S. Ando,, K. Matsumoto, and, K. Sugimoto. 1998. Functional and physical interaction between Rad24 and Rfc5 in the yeast checkpoint pathway. Mol. Cell. Biol. 18:54855491.
194. Shiomi, Y.,, A. Shinozaki,, D. Nakada,, K. Sugimoto,, J. Usukura,, C. Obuse, and, T. Tsurimoto. 2002. Clamp and clamp loader structures of the human checkpoint protein complexes, Rad9–1-1 and Rad17-RFC. Genes Cells 7:861868.
195. Siede, W.,, A. S. Friedberg,, I. Dianova, and, E. C. Friedberg. 1994. Characterization of G1 checkpoint control in the yeast Saccharomyces cerevisiae following exposure to DNA-damaging agents. Genetics 138:271281.
196. Siede, W.,, A. S. Friedberg, and, E. C. Friedberg. 1993. RAD9- dependent G1 arrest defines a second checkpoint for damaged DNA in the cell cycle of Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 90:79857989.
197. Siede, W.,, A. A. Friedl,, I. Dianova,, F. Eckardt-Schupp, and, E. C. Friedberg. 1996. The Saccharomyces cerevisiae Ku autoantigen homo-logue affects radiosensitivity only in the absence of homologous recombination. Genetics 142:91102.
198. Siede, W.,, G. Nusspaumer,, V. Portillo,, R. Rodriguez, and, E. C. Friedberg. 1996. Cloning and characterization of RAD17, a gene controlling cell cycle responses to DNA damage in Saccharomyces cerevisiae. Nucleic Acids Res. 24:16691675.
199. Silva, E.,, S. Tiong,, M. Pedersen,, E. Homola,, A. Royou,, B. Fa-sulo,, G. Siriaco, and, S. D. Campbell. 2004. ATM is required for telomere maintenance and chromosome stability during Drosophila development. Curr. Biol. 14:13411347.
200. Smith, G. C.,, R. B. Cary,, N. D. Lakin,, B. C. Hann,, S. H. Teo,, D. J. Chen, and, S. P. Jackson. 1999. Purification and DNA binding properties of the ataxia-telangiectasia gene product ATM. Proc. Natl. Acad. Sci. USA 96:1113411139.
201. Song, Y.-H.,, G. Mirey,, M. Betson,, D. A. Haber, and, J. Settleman. 2004. The Drosophila ATM ortholog, dATM, mediates the response to ionizing radiation and to spontaneous DNA damage during development. Curr. Biol. 14:13541359.
202. Stewart, E.,, C. R. Chapman,, F. Al-Khodairy,, A. M. Carr, and, T. Enoch., 197. rqh1+, a fission yeast gene related to the Bloom’s and Werner’s syndrome genes, is required for reversible S phase arrest. EMBO J. 16:26822692.
203. Stewart, G. S.,, R. S. Maser,, T. Stankovic,, D. A. Bressan,, M. I. Kaplan,, N. G. J. Jaspers,, A. Raams,, P. J. Byrd,, J. H. J. Petrini, and, A. M. R. Taylor. 1999. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99: 577587.
204. St. Onge, R. P.,, B. D. Besley,, J. L. Pelley, and, S. Davey. 2003. A role for the phosphorylation of hRad9 in checkpoint signaling. J. Biol. Chem. 278:2662026628.
205. St. Onge, R. P.,, C. M. Udell,, R. Casselman, and, S. Davey. 1999. The human G2 checkpoint control protein hRAD9 is a nuclear phospho-protein that forms complexes with hRAD1 and hHUS1. Mol. Biol. Cell 10:19851995.
206. Suzuki, K.,, S. Kodama, and, M. Watanabe. 1999. Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation. J. Biol. Chem. 274:2557125575.
207. Tan, S., and, T. S.-F. Wang. 2000. Analysis of fission yeast primase defines the checkpoint responses to aberrant S phase initiation. Mol. Cell. Biol. 20:78537866.
208. Thelen, M. P.,, K. Onel, and, W. K. Holloman. 1994. The REC1 gene of Ustilago maydis involved in the cellular response to DNA damage encodes an exonuclease. J. Biol. Chem. 269:747754.
209. Thelen, M. P.,, C. Venclovas, and, K. Fidelis. 1999. A sliding clamp model for the Rad1 family of cell cycle checkpoint proteins. Cell 96:769770.
210. Udell, C. M.,, S. K. Lee, and, S. Davey. 1998. HRAD1 and MRAD1 encode mammalian homologues of the fission yeast rad1+ cell cycle checkpoint control gene. Nucleic Acids Res. 26:39713976.
211. Ünsal-Kaçmaz, K.,, A. M. Makhov,, J. D. Griffith, and, A. Sancar. 2002. Preferential binding of ATR protein to UV-damaged DNA. Proc. Natl. Acad. Sci. USA 99:66736678.
212. Ünsal-Kaçmaz, K., and, A. Sancar. 2004. Quarternary structure of ATR and effects of ATRIP and replication protein A on its DNA binding and kinase activity. Mol. Cell. Biol. 24:12921300.
213. Uziel, T.,, Y. Lerenthal,, L. Moyal,, Y. Andegeko,, L. Mittelman, and, Y. Shiloh. 2003. Requirement of the MRN complex for ATM activation by DNA damage. EMBO J. 22:56125621.
214. Valenzuela, M. T.,, R. Guerrero,, M. I. Núñez,, J. M. R. de Almodóvar,, M. Sarker,, G. de Murcia, and, F. J. Oliver. 2002. PARP-1 modifies the effectiveness of p53-mediated DNA damage response. Oncogene 21:11081116.
215. van Brabant, A. J.,, C. D. Buchanan,, E. Charboneau,, W. L. Fang-man, and, B. J. Brewer. 2001. An origin-deficient yeast artificial chromosome triggers a cell cycle checkpoint. Mol. Cell 7:705713.
216. Venclovas, C., and, M. P. Thelen. 2000. Structure-based predictions of Rad1, Rad9, Hus1 and Rad17 participation in sliding clamp and clamp-loading complexes. Nucleic Acids Res. 28:24812493.
217. Volkmer, E., and, L. M. Karnitz. 1999. Human homolog of Schizosaccharomyces pombe Rad1, Hus1, and Rad9 form a DNA damage-responsive protein complex. J. Biol. Chem. 274:567570.
218. von Deimling, F.,, J. M. Scharf,, T. Liehr,, M. Rothe,, A.-R. Kelter,, P. Albers,, W. F. Dietrich,, L. M. Kunkel,, N. Wernert, and, B. Wirth. 1995. Human and mouse RAD17 genes: identification, localization, genomic structure and histological expression pattern in normal testis and seminoma. Hum. Genet. 105:1727.
219. Waga, S., and, B. Stillman. 1998. The DNA replication fork in eukaryotic cells. Annu. Rev. Biochem. 67:721751.
220. Wakayama, T.,, T. Kondo,, S. Ando,, K. Matsumoto, and, K. Sug-imoto. 2001. Pie1, a protein interacting with Mec1, controls cell growth and checkpoint responses in Saccharomyces cerevisiae. Mol. Cell. Biol. 21:755764.
221. Wan, S.,, H. Capasso, and, N. Walworth. 1999. The topoisomerase I poison camptothecin generates a Chk1-dependent DNA damage checkpoint signal in fission yeast. Yeast 15:821828.
222. Wang, H., and, S. J. Elledge. 1999. DRC1, DNA replication and checkpoint protein 1, functions with DBP11 to control DNA replication and the S-phase checkpoint in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 96:38243829.
223. Wang, H., and, S. J. Elledge. 2002. Genetic and physical interactions between DPB11 and DDC1 in the yeast DNA damage response pathway. Genetics 160:12951304.
224. Wang, S.,, M. Guo,, H. Ouyang,, X. Li,, C. Cordon-Cardo,, A. Kuri-masa,, D. J. Chen,, Z. Fuks,, C. C. Ling, and, G. C. Li. 2000. The catalytic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest. Proc. Natl. Acad. Sci. USA 97: 15841588.
225. Wang, X.,, K. Ohnishi,, A. Takahashi, and, T. Ohnishi. 1998. Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation. Oncogene 17:28192825.
226. Wang, Y.,, A. R. Perrault, and, G. Iliakis. 1997. Down-regulation of DNA replication in extracts of camptothecin-treated cells: activation of an S-phase checkpoint. Cancer Res. 57:16541659.
227. Wang, Z. Q.,, L. Stingl,, C. Morrison,, M. Jantsch,, M. Los,, K. Schulze-Osthoff, and, E. F. Wagner. 1997. PARP is important for genomic stability but dispensable in apoptosis. Genes Dev. 11: 23472358.
228. Watanabe, K.,, J. Morishita,, K. Umezu,, K. Shirahige, and, H. Maki. 2002. Involvement of RAD9-dependent damage checkpoint control in arrest of cell cycle, induction of cell death, and chromosome instability caused by defects in origin recognition complex in Saccharomyces cerevisiae. Eukaryot. Cell 1:200212.
229. Weinberger, M.,, L. Ramachandran, and, W. C. Burhans. 2003. Apoptosis in yeasts. IUBMB Life 55:467472.
230. Weinert, T. A., 1992. Dual cell cycle checkpoints sensitive to chromosome replication and DNA damage in the budding yeast Saccharomyces cerevisiae. Radiat. Res. 132:141143.
231. Weinert, T. A., and, L. H. Hartwell. 1993. Cell cycle arrest of cdc mutants and specificity of the RAD9 checkpoint. Genetics 134:6380.
232. Weinert, T. A., and, L. H. Hartwell. 1988. The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. Science 241:317322.
233. Weinert, T. A.,, G. L. Kiser, and, L. H. Hartwell. 1994. Mitotic checkpoint genes in budding yeast and the dependence of mitosis on DNA replication and repair. Genes Dev. 8:652665.
234. Weiss, R. S.,, T. Enoch, and, P. Leder. 2000. Inactivation of mouse Hus1 results in genomic instability and impaired responses to genotoxic stress. Genes Dev. 14:18861898.
235. Weiss, R. S.,, C. F. Kostrub,, T. Enoch, and, P. Leder. 1999. Mouse Hus1, a homolog of the Schizosaccharomyces pombe hus1 + cell cycle checkpoint gene. Genomics 59:3239.
236. Weiss, R. S.,, P. Leder, and, C. Vaziri. 2003. Critical role for mouse Hus1 in an S-phase DNA damage cell cycle checkpoint. Mol. Cell. Biol. 23: 791803.
237. Wieler, S.,, J. P. Gagne,, H. Vaziri,, G. G. Poirier, and, S. Benchi-mol. 2003. Poly(ADP-ribose) polymerase-1 is a positive regulator of the p53-mediated G1 arrest response following ionizing radiation. J. Biol. Chem. 278:1891418921.
238. Wold, M. S., 1997. Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Annu. Rev. Biochem. 66:6192.
239. Xu, B.,, S.-T. Kim,, D.-S. Lim, and, M. B. Kastan. 2002. Two molecularly distinct G2/M checkpoints are induced by ionizing irradiation. Mol. Cell. Biol. 22:10491059.
240. Yamaizumi, M., and, T. Sugano. 1994. U.v.-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes independent of the cell cycle. Oncogene 9:27752784.
241. Yan, T.,, J. E. Schupp,, H.-S. Hwang,, M. W. Wagner,, S. E. Berry,, S. Strickfaden,, M. L. Veigl,, W. D. Sedwick,, D. A. Boothman, and, T. J. Kinsella. 2001. Loss of DNA mismatch repair imparts defective cdc2 signaling and G2 arrest responses without altering survival after ionizing radiation. Cancer Res. 61:82908297.
242. Ye, X.,, A. A. Franco,, H. Santos,, D. M. Nelson,, P. D. Kaufman, and, P. D. Adams. 2003. Defective S phase chromatin assembly causes DNA damage, activation of the S phase checkpoint, and S phase arrest. Mol. Cell 11:341351.