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Chapter 21 : Cell Cycle Checkpoints

Authors: C. Friedberg Errol1, C. Walker Graham2, Siede Wolfram3, D. Wood Richard4, A. Schultz Roger5, Ellenberger Tom6
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Affiliations: 1: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; 2: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; 3: Department of Cell Biology and Genetics, University of North Texas Health Science Center, Fort Worth, Texas; 4: Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania; 5: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; 6: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts
Content Type: Reference
Publication Year: 2006

Category: Microbial Genetics and Molecular Biology

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Abstract:

This chapter illustrates the strategies of signal amplification and transmission and the multiple targets in cell cycle and repair in various species. The signal transduction mechanisms rely on the activation of protein kinases as effector proteins by phosphorylation. Other proteins, termed mediators, are critical for converting sensor input into such kinase modification. The best-understood example for such collaboration is represented by the Rad53 kinase and Rad9 as its mediator of checkpoint activation in . It discusses the downstream targets that are regulated by the damage-sensing and signal transmission systems. The discussion of targets involved in cell cycle progression is separated from the discussion of targets affecting aspects of repair more directly. The chapter also discusses p53 in damage-signaling pathways, and presents an integrated view of various cell cycle checkpoints and their regulation. In conclusion, it is appropriate to mention at least two additional areas, which arguably can be classified as checkpoint responses; these are the active inhibition of transcription and translation in response to DNA damage.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Cell Cycle Checkpoints
Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–1
Domain structure of Rad53/Cds1/CHK2 kinases. Locations of FHA, kinase, and SQ/TQ-rich domains in the various orthologs are shown. The star indicates the highly conserved activation loop in each ortholog. aa, amino acids. (Adapted from reference .)
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Figure 21–1

Domain structure of Rad53/Cds1/CHK2 kinases. Locations of FHA, kinase, and SQ/TQ-rich domains in the various orthologs are shown. The star indicates the highly conserved activation loop in each ortholog. aa, amino acids. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–2
Role of Rad9 as a mediator of Rad53 kinase activation. In this model, activation of Mec1 (targeted by Lcd1) has already occurred and substrate selection by interaction with damage sensor proteins has been enabled, possibly by a mechanism similar to the one shown in Fig. 20–15. Mec1 phosphorylates Rad9, which binds near damaged DNA sites and forms dimers or multimers. Phosphorylated Rad9 is bound by Rad53. Rad53 will autophosphorylate in possibly after initial direct phosphorylation and activation by Mec1. Hyperphosphorylated and fully active Rad53 species emerge which separate from Rad9, and Rad9 is free to interact again with hypophosphorylated Rad53.
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Figure 21–2

Role of Rad9 as a mediator of Rad53 kinase activation. In this model, activation of Mec1 (targeted by Lcd1) has already occurred and substrate selection by interaction with damage sensor proteins has been enabled, possibly by a mechanism similar to the one shown in Fig. 20–15. Mec1 phosphorylates Rad9, which binds near damaged DNA sites and forms dimers or multimers. Phosphorylated Rad9 is bound by Rad53. Rad53 will autophosphorylate in possibly after initial direct phosphorylation and activation by Mec1. Hyperphosphorylated and fully active Rad53 species emerge which separate from Rad9, and Rad9 is free to interact again with hypophosphorylated Rad53.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–3
Domain structure of Rad9. The locations of the tandem BRCT repeat, potential nuclear localization signals (NLS), the Rad53-interacting region, and an SC cluster domain (SCD) are shown. Additionally, potential phosphorylation sites for the budding-yeast Cdk Cdc28 and for PI3 kinase (PI3K)-like kinases such as Mec1 are indicated. (Adapted from reference .)
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Figure 21–3

Domain structure of Rad9. The locations of the tandem BRCT repeat, potential nuclear localization signals (NLS), the Rad53-interacting region, and an SC cluster domain (SCD) are shown. Additionally, potential phosphorylation sites for the budding-yeast Cdk Cdc28 and for PI3 kinase (PI3K)-like kinases such as Mec1 are indicated. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–4
Similarities of the roles of mammalian MDC1 and 53BP1. Both are phosphorylated by ATM, both are suspected to be possible mediators of ATM-dependent CHK2 activation, and both interact physically and functionally with -γ-H2AX. CHK2 activation by autophosphorylation is not shown here (see Fig. 21–3 ). Phosphorylation of H2AX depends on ATM following DSB induction and on ATR and its targeting factor ATRIP following UV radiation. MDC1 interacts with the MRN complex and strengthens ATM binding to DSB.
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Figure 21–4

Similarities of the roles of mammalian MDC1 and 53BP1. Both are phosphorylated by ATM, both are suspected to be possible mediators of ATM-dependent CHK2 activation, and both interact physically and functionally with -γ-H2AX. CHK2 activation by autophosphorylation is not shown here (see Fig. 21–3 ). Phosphorylation of H2AX depends on ATM following DSB induction and on ATR and its targeting factor ATRIP following UV radiation. MDC1 interacts with the MRN complex and strengthens ATM binding to DSB.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–5
Checkpoint kinase-mediator relationships in selected eukaryotic organisms. ?, unknown or unproven candidate. (Adapted from reference .)
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Figure 21–5

Checkpoint kinase-mediator relationships in selected eukaryotic organisms. ?, unknown or unproven candidate. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–6
UV irradiation enhances the half-life of p53 protein. Proteins were labeled with [S] methionine in mouse cells before treatment of the cells with UV radiation at 0 (—UV) or 10 (+UV) J/m. Relative steady-state levels of p53 were detected by immunoprecipitation at various time points during postirradiation incubation in the presence of nonradioactive methionine. These chase periods are indicated on the axis. (Adapted from reference .)
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Figure 21–6

UV irradiation enhances the half-life of p53 protein. Proteins were labeled with [S] methionine in mouse cells before treatment of the cells with UV radiation at 0 (—UV) or 10 (+UV) J/m. Relative steady-state levels of p53 were detected by immunoprecipitation at various time points during postirradiation incubation in the presence of nonradioactive methionine. These chase periods are indicated on the axis. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–7
Selected post-translational modifications of p53 in relation to domain structure and protein interactions in response to various stresses that may or may not be associated with geno-toxicity. The protein’s transactivation, SH3 (SRC homology 3-like), DNA-binding, tetramerization (Tet), regulatory domains (Reg), nuclear localization signal (NLS), and nuclear export signal (NES) are shown. Regions of protein interaction are indicated below the map. Post-translational modification sites are indicated for phosphorylation (P), acetylation (Ac), methylation (Me), ubiquitination/NEDDylation (Ub, Ub/N), and sumoylation (SUMO). Putative modifying enzymes are listed (? indicates an unknown enzyme). In the upper half, the available studies of the influence of the treatments listed to the left on the modification of each site are summarized. An open symbol stands for no detectable modification, and a solid symbol stands for an increase in modification under the condition listed. A down arrow in a symbol stands for downregulation. A solid symbol with asterisks indicates ATM-dependent phosphorylation. (Adapted from reference and C. W. Anderson, personal communication.)
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Figure 21–7

Selected post-translational modifications of p53 in relation to domain structure and protein interactions in response to various stresses that may or may not be associated with geno-toxicity. The protein’s transactivation, SH3 (SRC homology 3-like), DNA-binding, tetramerization (Tet), regulatory domains (Reg), nuclear localization signal (NLS), and nuclear export signal (NES) are shown. Regions of protein interaction are indicated below the map. Post-translational modification sites are indicated for phosphorylation (P), acetylation (Ac), methylation (Me), ubiquitination/NEDDylation (Ub, Ub/N), and sumoylation (SUMO). Putative modifying enzymes are listed (? indicates an unknown enzyme). In the upper half, the available studies of the influence of the treatments listed to the left on the modification of each site are summarized. An open symbol stands for no detectable modification, and a solid symbol stands for an increase in modification under the condition listed. A down arrow in a symbol stands for downregulation. A solid symbol with asterisks indicates ATM-dependent phosphorylation. (Adapted from reference and C. W. Anderson, personal communication.)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–8
IR-induced p53 phosphorylation at certain sites is reduced in AT cells. Immunoblots with the indicated phosphospecific polyclonal antibodies were performed at the times indicated following 8-Gy γ-irradiation (IR) treatment of human lymphoblast cultures. Reduced phosphorylation was found for Ser9, Ser15, Ser20, and Ser46 in AT cells but not or much less so for Ser6, Ser33, Ser315, and Ser392. The first row shows the level of total p53 detected with a monoclonal antibody. (Adapted from reference .)
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Figure 21–8

IR-induced p53 phosphorylation at certain sites is reduced in AT cells. Immunoblots with the indicated phosphospecific polyclonal antibodies were performed at the times indicated following 8-Gy γ-irradiation (IR) treatment of human lymphoblast cultures. Reduced phosphorylation was found for Ser9, Ser15, Ser20, and Ser46 in AT cells but not or much less so for Ser6, Ser33, Ser315, and Ser392. The first row shows the level of total p53 detected with a monoclonal antibody. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–9
Defective G arrest in p53-deficient cells following exposure to IR. (A) The dot diagram visualizes the distribution of cells among different cycle stages in an unsynchronized culture of embryonic mouse fibroblasts before and after X-ray treatment. Cells were pulse-labeled with BrdU and analyzed by flow cytometry (see Fig. 20–8). The axis indicates total DNA content (detected by propidium iodide staining), whereas the axis shows the amount of incorporated BrdU (detected by binding of a BrdU-specific antibody conjugated to a fluorescent dye). Cells in S phase are characterized by high BrdU levels and an intermediate total DNA content. A depletion of cells in S phase is evident 16 h after irradiation with 2 Gy of normal cells and those carrying a heterozygous p53 defect (). However, there is no indication of G/S arrest in cells homozygous for a p53 defect (— / —). (B) This type of analysis is quantitated by plotting the percentage of cells remaining in S phase 16 h after irradiation with 0 or 2 Gy. (Adapted from reference .)
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Figure 21–9

Defective G arrest in p53-deficient cells following exposure to IR. (A) The dot diagram visualizes the distribution of cells among different cycle stages in an unsynchronized culture of embryonic mouse fibroblasts before and after X-ray treatment. Cells were pulse-labeled with BrdU and analyzed by flow cytometry (see Fig. 20–8). The axis indicates total DNA content (detected by propidium iodide staining), whereas the axis shows the amount of incorporated BrdU (detected by binding of a BrdU-specific antibody conjugated to a fluorescent dye). Cells in S phase are characterized by high BrdU levels and an intermediate total DNA content. A depletion of cells in S phase is evident 16 h after irradiation with 2 Gy of normal cells and those carrying a heterozygous p53 defect (). However, there is no indication of G/S arrest in cells homozygous for a p53 defect (— / —). (B) This type of analysis is quantitated by plotting the percentage of cells remaining in S phase 16 h after irradiation with 0 or 2 Gy. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–10
The kinase activity of a Cdk2-cyclin A complex is inhibited by increasing amounts of p21. Kinase activity is measured by histone H1 phosphorylation with P (H1-p). (Adapted from reference .)
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Figure 21–10

The kinase activity of a Cdk2-cyclin A complex is inhibited by increasing amounts of p21. Kinase activity is measured by histone H1 phosphorylation with P (H1-p). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–11
Scheme for p53-mediated maintenance of G/S arrest in response to DNA damage. As described, DNA damage activates the PI3 kinase-related ATM and ATR kinases, which in turn activate CHK1 and CHK2. Modification of p53, assisted by MDM2 phosphorylation, results in p53 activation and stabilization of its level. The transcription of the gene is increased. Accumulated p21 blocks CDK2-cyclin E (Cyc E) and other Cdk activities. As a consequence, RB1 is not hyperphosphorylated and the E2F transcription factor controlling S-phase-specific transcripts is not released. (Adapted from reference .)
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Figure 21–11

Scheme for p53-mediated maintenance of G/S arrest in response to DNA damage. As described, DNA damage activates the PI3 kinase-related ATM and ATR kinases, which in turn activate CHK1 and CHK2. Modification of p53, assisted by MDM2 phosphorylation, results in p53 activation and stabilization of its level. The transcription of the gene is increased. Accumulated p21 blocks CDK2-cyclin E (Cyc E) and other Cdk activities. As a consequence, RB1 is not hyperphosphorylated and the E2F transcription factor controlling S-phase-specific transcripts is not released. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–12
Scheme for rapid G arrest mechanisms in response to DNA damage. Following activation of effector kinases CHK1 and CHK2, CDC25A phosphatase is phosphorylated (left). Phosphorylation results in recognition and ubiquitylation of CDC25A by the SCF complex and ultimately to degradation by the proteasome. The absence of phosphatase CDC25 leads to a failure to dephosphorylate and activate CDK2. One consequence is the inability of CDC45 to bind to the origin (ORI) recognition complex, a necessary precondition for replicon initiation. The cell will not enter S phase from G or, if already in S phase, will not continue origin activation. The other proposed mechanism (right) is based on damage-induced destabilization of the cyclin D1 (CycD1) subunit of CDK4 by an unknown mechanism. In many mammalian somatic cells, abundant cyclin D1 is used to bind p21 at a stage where the dependency of cell cycle progression switches from the CDK4-cyclin D1 to the CDK2-cyclin E (Cyc E) complex (see Fig. 20–1). Destabilization of cyclin D1 results in release of p21 from this reservoir, and the CDK2-cyclin E complex will be inactivated. (Ub, ubiquitin) (Adapted from reference .)
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Figure 21–12

Scheme for rapid G arrest mechanisms in response to DNA damage. Following activation of effector kinases CHK1 and CHK2, CDC25A phosphatase is phosphorylated (left). Phosphorylation results in recognition and ubiquitylation of CDC25A by the SCF complex and ultimately to degradation by the proteasome. The absence of phosphatase CDC25 leads to a failure to dephosphorylate and activate CDK2. One consequence is the inability of CDC45 to bind to the origin (ORI) recognition complex, a necessary precondition for replicon initiation. The cell will not enter S phase from G or, if already in S phase, will not continue origin activation. The other proposed mechanism (right) is based on damage-induced destabilization of the cyclin D1 (CycD1) subunit of CDK4 by an unknown mechanism. In many mammalian somatic cells, abundant cyclin D1 is used to bind p21 at a stage where the dependency of cell cycle progression switches from the CDK4-cyclin D1 to the CDK2-cyclin E (Cyc E) complex (see Fig. 20–1). Destabilization of cyclin D1 results in release of p21 from this reservoir, and the CDK2-cyclin E complex will be inactivated. (Ub, ubiquitin) (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–13
Influence of Rad53-dependent checkpoint mechanisms on DNA replication in the presence of MMS damage. G-synchronized cells with density-labeled DNA are released into MMS-containing medium. Progression of DNA synthesis initiated at an early replicon (ARS607) of chromosome X is followed by separation of chromosomal DNA into heavy (HH) and intermediate-density (HL, heavy-light) fractions and the use of probes 1 to 6 to detect the presence of sequences downstream of the ARS607 origin. In the wild type (WT), a slow but ultimately complete shift from HH to HL density is found throughout the region, indicating complete replication of the 70-kb monitored area. Two differences are found in the checkpoint-deficient mutants (as well as in mutants [not shown]). At 60 min, there is evidence of a progressing replication fork entering distal from the studied region (from the right of area 6 [arrow 1]). The corresponding origin is silenced in the MMS-treated wild type. Also, there is evidence of a fraction of DNA that is never completely replicated (clearly visible if area 3 at 90 through 240 min is compared to the wild type [arrow 2]). This is indicative of replication fork collapse. (Adapted from reference .)
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Figure 21–13

Influence of Rad53-dependent checkpoint mechanisms on DNA replication in the presence of MMS damage. G-synchronized cells with density-labeled DNA are released into MMS-containing medium. Progression of DNA synthesis initiated at an early replicon (ARS607) of chromosome X is followed by separation of chromosomal DNA into heavy (HH) and intermediate-density (HL, heavy-light) fractions and the use of probes 1 to 6 to detect the presence of sequences downstream of the ARS607 origin. In the wild type (WT), a slow but ultimately complete shift from HH to HL density is found throughout the region, indicating complete replication of the 70-kb monitored area. Two differences are found in the checkpoint-deficient mutants (as well as in mutants [not shown]). At 60 min, there is evidence of a progressing replication fork entering distal from the studied region (from the right of area 6 [arrow 1]). The corresponding origin is silenced in the MMS-treated wild type. Also, there is evidence of a fraction of DNA that is never completely replicated (clearly visible if area 3 at 90 through 240 min is compared to the wild type [arrow 2]). This is indicative of replication fork collapse. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–14
Parallel pathways regulate the mammalian IR-induced S-phase checkpoint(s). One well-understood pathway functions by degradation of the CDC25 phosphatase following ATM-mediated phosphorylation. The MRN complex, BRCA1, and FANCD2 seem to be involved in alternative pathways. As discussed in the text, an important target is SMC1, which is phosphorylated by ATM in a reaction that depends on the MRN complex and BRCA1. The mechanism of SMC1 and FANCD2 action is unknown.
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Figure 21–14

Parallel pathways regulate the mammalian IR-induced S-phase checkpoint(s). One well-understood pathway functions by degradation of the CDC25 phosphatase following ATM-mediated phosphorylation. The MRN complex, BRCA1, and FANCD2 seem to be involved in alternative pathways. As discussed in the text, an important target is SMC1, which is phosphorylated by ATM in a reaction that depends on the MRN complex and BRCA1. The mechanism of SMC1 and FANCD2 action is unknown.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–15
Regulation of G/M arrest in response to DNA damage. Dephosphorylation of Tyr15 (and Thr14 [not shown]) is required for activity of the mitotic Cdk Cdc2 of Wee1 and Mik1 kinases phosphorylate Tyr15, and Cdc25 is the activating phosphatase. Cdc25 appears to be the main target of DNA damage regulation. It is phosphorylated by the Mec1/ATR homolog Rad3. Phosphorylated Cdc25 is subject to binding by the 14-3-3 protein Rad24 and is actively excluded from the nucleus.
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Figure 21–15

Regulation of G/M arrest in response to DNA damage. Dephosphorylation of Tyr15 (and Thr14 [not shown]) is required for activity of the mitotic Cdk Cdc2 of Wee1 and Mik1 kinases phosphorylate Tyr15, and Cdc25 is the activating phosphatase. Cdc25 appears to be the main target of DNA damage regulation. It is phosphorylated by the Mec1/ATR homolog Rad3. Phosphorylated Cdc25 is subject to binding by the 14-3-3 protein Rad24 and is actively excluded from the nucleus.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–16
Regulation of mammalian G/M arrest in response to DNA damage. Part of this scheme (right half) depicts the regulation of CDC25 phosphatase, as shown in more detail for the paradigm in Fig. 21–15 . To the left, the role of p53-mediated transcription in arrest maintenance is indicated. Enhanced transcription of the and genes results in increased inactivation and cytoplasmic sequestration of CDK1 (i.e., CDC2). (Adapted from reference .)
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Figure 21–16

Regulation of mammalian G/M arrest in response to DNA damage. Part of this scheme (right half) depicts the regulation of CDC25 phosphatase, as shown in more detail for the paradigm in Fig. 21–15 . To the left, the role of p53-mediated transcription in arrest maintenance is indicated. Enhanced transcription of the and genes results in increased inactivation and cytoplasmic sequestration of CDK1 (i.e., CDC2). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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Figure 21–17
Branched pathway of M-phase arrest in in response to DNA damage. In response to DNA strand breakage and the resulting Mec1 activation, branches mediated by the effector kinases Chk1 and Rad53 represent different mechanisms and timing of arrest. The Chk1 pathway blocks cohesin cleavage and thus chromosome separation at the metaphase-anaphase transition. The Rad53 pathway inhibits mitotic exit by preventing B-type cyclin degradation and other associated events. In both cases, substrate recognition and protein degradation by the anaphase-promoting complex (APC) are impaired.
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Image of Figure 21–17
Figure 21–17

Branched pathway of M-phase arrest in in response to DNA damage. In response to DNA strand breakage and the resulting Mec1 activation, branches mediated by the effector kinases Chk1 and Rad53 represent different mechanisms and timing of arrest. The Chk1 pathway blocks cohesin cleavage and thus chromosome separation at the metaphase-anaphase transition. The Rad53 pathway inhibits mitotic exit by preventing B-type cyclin degradation and other associated events. In both cases, substrate recognition and protein degradation by the anaphase-promoting complex (APC) are impaired.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Cell Cycle Checkpoints, p 779-815. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch21
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1. Abramova, N. A.,, J. Russell,, M. Botchan, and, R. Li. 1997. Interaction between replication protein A and p53 is disrupted after UV damage in a DNA repair-dependent manner. Proc. Natl. Acad. Sci. USA 94 :7186– 7191.
2. Agami, R., and, R. Bernards. 2000. Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell 102 :55– 66.
3. Ahn, J.,, M. Urist, and, C. Prives. 2004. The Chk2 protein kinase. DNA Repair 3 :1039– 1047.
4. Ahn, J.-Y.,, X. Li,, H. L. Davis, and, C. E. Canman. 2002. Phosphorylation of threonine 68 promotes oligomerization and autophosphorylation of the Chk2 protein kinase via the forkhead-associated domain. J. Biol. Chem. 277 :19389– 19395.
5. Akyüz, N.,, G. S. Boehden,, S. Süsse,, A. Rimek,, U. Preuss,, K.-H. Scheidtmann, and, L. Wiesmüller. 2002. DNA substrate dependence of p53-mediated regulation of double-strand break repair. Mol. Cell. Biol. 22 :6306– 6317.
6. Alcasabas, A. A.,, A. J. Osborn,, J. Bachant,, F. Hu,, P. J. H. Werler,, K. Bousset,, K. Furuya,, J. F. X. Diffley,, A. M. Carr, and, S. J. Elledge. 2001. Mrc1 transduces signals of DNA replication stress to activate Rad53. Nat. Cell Biol. 3 :958– 965.
7. 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 :147– 160.
8. 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 :2401– 2415.
9. Allison, S., and, J. Millner. 2004. Remodelling chromatin on a global scale: a novel protective function of p53. Carcinogenesis 25 :1551– 1557.
10. Amon, A.,, U. Surana,, I. Muroff, and, K. Nasmyth. 1992. Regulation of p34 cdc28 tyrosine phosphorylation is not required for entry into mitosis in S. cerevisiae. Nature 355 :365– 368.
11. An, W.,, J. Kim, and, G. S. Roeder. 2004. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 117 :735– 748.
12. Anderson, C. W., and, E. Appella. 2003. Signaling to the p53 suppressor through pathways activated by genotoxic and non-genotoxic stresses, p. 237– 247. In R. A. Bradshaw and, E. Dennis (ed.), Handbook of Cell Signaling, vol., 3. Academic Press, Inc., New York, N.Y.
13. Anderson, L.,, C. Henderson, and, Y. Adachi. 2001. Phosphorylation and rapid relocalization of 53BP1 to nuclear foci upon DNA damage. Mol. Cell. Biol. 21 :1719– 1729.
14. Anderson, M. E.,, B. Woelker,, M. Reed,, P. Wang, and, P. Tegtmeyer. 1997. Reciprocal interference between the sequence-specific core and nonspecific C-terminal DNA binding domains of p53: implications for regulation. Mol. Cell. Biol. 17 :6255– 6264.
15. Appella, E., and, C. W. Anderson. 2001. Post-translational modifications and activation of p53 by genotoxic stresses. Eur. J. Biochem. 268 : 2764– 2772.
16. Arlt, M. F.,, B. Xu,, S. G. Durkin,, A. M. Casper,, M. B. Kastan, and, T. W. Glover. 2004. BRCA1 is required for common-fragile-site stability via its G2/M checkpoint function. Mol. Cell. Biol. 24 :6701– 6709.
17. Ashcroft, M.,, M. H. G. Kubbutat, and, K. H. Vousden. 1999. Regulation of p53 function and stability by phosphorylation. Mol. Cell. Biol. 19 : 1751– 1758.
18. Asher, G.,, J. Lotem,, R. Kama,, L. Sachs, and, Y. Shaul. 2002. NQO1 stabilizes p53 through a distinct pathway. Proc. Natl. Acad. Sci. USA 99 :3099– 3104.
19. Aubrecht, J.,, M. B. Secretan,, A. J. R. Bishop, and, R. H. Schiestl. 1999. Involvement of p53 in X-ray induced intrachromosomal recombination in mice. Carcinogenesis 20 :2229– 2236.
20. Avantaggiati, M. L.,, V. Ogryzko,, K. Gardner,, A. Giordano,, A. S. Levine, and, K. Kelly. 1997. Recruitment of p300/CBP in p53-dependent signal pathways. Cell 89 :1175– 1184.
21. Aylon, Y., and, M. Kupiec. 2003. The checkpoint protein Rad24 of Saccharomyces cerevisiae is involved in processing double-strand break ends and in recombination partner choice. Mol. Cell. Biol. 23 :6585– 6596.
22. Badie, C.,, J. E. Itzhaki,, M. J. Sullivan,, A. J. Carpenter, and, A. C. G. Porter. 2000. Repression of CDK1 and other genes with CDE and CHR promoter elements during DNA damage-induced G 2/M arrest in human cells. Mol. Cell. Biol. 20 :2358– 2366.
23. 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 :1674– 1677.
24. Baroni, E.,, V. Viscardi,, H. Cartagena-Lirola,, G. Lucchini, and, M. P. Longhese. 2004. The functions of budding yeast Sae2 in the DNA damage response require Mec1- and Tel1-dependent phosphorylation. Mol. Cell. Biol. 24 :4151– 4165.
25. Bartek, J.,, J. Falck, and, J. Lukas. 2001. Chk2 kinase—a busy messenger. Nat. Rev. Mol. Cell Biol. 2 :877– 886.
26. Bartek, J.,, C. Lukas, and, J. Lukas. 2004. Checking on DNA damage in S phase. Nat. Rev. Mol. Cell Biol. 5 :793– 804.
27. Bartek, J., and, J. Lukas. 2001. Mammalian G1- and S-phase checkpoints in response to DNA damage. Curr. Opin. Cell Biol. 13 :738– 747.
28. Bartrand, A. J.,, D. Iyasu, and, G. S. Brush. 2004. DNA stimulates Mec1-mediated phosphorylation of replication protein A. J. Biol. Chem. 279 : 26762– 26767.
29. Bashkirov, V. I.,, E. V. Bashkirova,, E. Haghnazari, and, W. D. Heyer. 2003. Direct kinase-to-kinase signaling mediated by the FHA phosphoprotein recognition domain of the Dun1 DNA damage checkpoint kinase. Mol. Cell. Biol. 23 :1441– 1452.
30. Bashkirov, V. I.,, J. S. King,, E. V. Bashkirova,, J. Schmuckli-Maurer, and, W.-D. Heyer. 2000. DNA repair protein Rad55 is a terminal substrate of the DNA damage checkpoints. Mol. Cell. Biol. 20 :4393– 4404.
31. Baskaran, R.,, L. D. Wood,, L. L. Whitaker,, C. E. Canman,, S. E. Morgan,, Y. Xu,, C. Barlow,, D. Baltimore,, A. Wynshaw-Boris,, M. B. Kastan, and, J. Y. J. Wang. 1997. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 387 : 516– 519.
32. Baudier, J.,, C. Delphin,, D. Grunwald,, S. Khochbin, and, J. J. Lawrence. 1992. Characterization of the tumor suppressor protein p53 as a protein kinase C substrate and a S100b-binding protein. Proc. Natl. Acad. Sci. USA 89 :11627– 11631.
33. Bell, D. W.,, J. M. Varley,, T. E. Szydlo,, D. H. Kang,, D. C. R. Wahrer,, K. E. Shannon,, M. Lubratovich,, S. J. Verselis,, K. J. Isselbacher,, J. F. Fraumeni,, J. M. Birch,, F. P. Li,, J. E. Garber, and, D. A. Haber. 1999. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286 :2528– 2531.
34. Bernal, J. A.,, R. Luna,, A. Espina,, I. Lázaro,, F. Ramos-Morales,, F. Romero,, C. Arias,, A. Silva,, M. Tortolero, and, J. A. Pintor-Toro. 2002. Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis. Nat. Genet. 32 :306– 311.
35. Bill, C. A.,, Y. Yu,, N. R. Miselis,, J. B. Little, and, J. A. Nickoloff. 1997. A role for p53 in DNA end rejoining by human cell extracts. Mutat. Res. 17 :21– 29.
36. Binz, S.,, A. Sheehan, and, M. Wold. 2004. Replication protein A phosphorylation and the cellular response to DNA damage. DNA Repair 3 : 1015– 1024.
37. Blasina, A.,, I. Van de Weyer,, M. C. Laus,, W. H. M. L. Luyten,, A. E. Parker, and, C. H. McGowan. 1999. A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Curr. Biol. 9 : 1– 10.
38. Blattner, C.,, T. Hay,, D. W. Meek, and, D. P. Lane. 2002. Hypophosphorylation of Mdm2 augments p53 stability. Mol. Cell. Biol. 22 :6170– 6182.
39. Blattner, C.,, E. Tobiasch,, M. Litfen,, H. J. Rahmsdorf, and, P. Herrlich. 1999. DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation. Oncogene 18 :1723– 1732.
40. Blaydes, J. P.,, M. G. Luciani,, S. Pospisilova,, H. M. -L. Ball,, B. Vojtesek, and, T. R. Hupp. 2001. Stoichiometric phosphorylation of human p53 at Ser 315 stimulates p53-dependent transcription. J. Biol. Chem. 276 : 4699– 4708.
41. Boddy, M. N.,, B. Furnari,, O. Mondesert, and, P. Russell. 1998. Replication checkpoint enforced by kinases Cds1 and Chk1. Science 280 :909– 912.
42. Boddy, M. N.,, A. Lopez-Girona,, P. Shanahan,, H. Interthal,, W.-D. Heyer, and, P. Russell. 2000. Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1. Mol. Cell. Biol. 20 :8758– 8766.
43. Boddy, M. N.,, P. Shanahan,, W. H. McDonald,, A. Lopez-Girona,, E. Noguchi,, I. J. Yates, and, P. Russell. 2003. Replication checkpoint kinase Cds1 regulates recombinational repair protein Rad60. Mol. Cell. Biol. 23 :5939– 5946.
44. 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 :666– 678.
45. Brooks, C. L., and, W. Gu. 2003. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr. Opin. Cell. Biol. 15 :164– 171.
46. Brown, A. L.,, C.-H. Lee,, J. K. Schwarz,, N. Mitiku,, H. Piwnica-Worms, and, J. H. Chung. 1999. 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.
47. Brown, E. J., and, D. Baltimore. 2003. Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev. 17 : 615– 628.
48. Brugarolas, J.,, C. Chandrasekaran,, J. I. Gordon,, D. Beach,, T. Jacks, and, G. Hannon. 1995. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377 :552– 557.
49. Bruins, W.,, E. Zwart,, L. D. Attardi,, T. Iwakuma,, E. M. Hooger-vorst,, R. B. Beems,, B. Miranda,, C. T. Van Oostrom,, J. Van Den Berg,, G. J. Van Den Aardweg,, G. Lozano,, H. Van Steeg,, T. Jacks, and, A. De Vries. 2004. Increased sensitivity to UV radiation in mice with a p53 point mutation at Ser389. Mol. Cell. Biol. 24 :8884– 8894.
50. Brush, G. S.,, C. W. Anderson, and, T. J. Kelly. 1994. The DNA-activated protein kinase is required for the phosphorylation of replication protein A during simian virus 40 DNA replication. Biochemistry 91 :12520– 12524.
51. Brush, G. S.,, D. M. Morrow,, P. Hieter, and, T. J. Kelly. 1996. The ATM homologue MEC1 is required for phosphorylation of replication protein A in yeast. Proc. Natl. Acad. Sci. USA 93 :15075– 15080.
52. Buchhop, S.,, M. K. Gibson,, X. W. Wang,, P. Wagner,, H.-W. Stürzbecher, and, C. C. Harris. 1997. Interaction of p53 with the human Rad51 protein. Nucleic Acids Res. 25 :3868– 3874.
53. Bulavin, D. V.,, S. A. Amundson, and, A. J. Fornace, Jr., 2002. p38 and Chk1 kinases: different conductors for the G 2/M checkpoint symphony. Curr. Opin. Cell Biol. 12 :92– 97.
54. Bulavin, D. V.,, Y. Higashimoto,, I. J. Popoff,, W. A. Gaarde,, V. Basrur,, O. Potapova,, E. Appella, and, A. J. Fornace, Jr., 2001. Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature 411 :102– 107.
55. Bulavin, D. V.,, S. Saito,, M. C. Hollander,, K. Sakaguchi,, C. W. Anderson,, E. Appella, and, A. J. Fornace, Jr., 1999. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J. 18 :6845– 6854.
56. Bunz, F.,, A. Dutriaux,, C. Lengauer,, T. Waldman,, S. Zhou,, J. P. Brown,, J. M. Sedivy,, K. W. Kinzler, and, B. Vogelstein. 1998. Requirement for p53 and p21 to sustain G 2 arrest after DNA damage. Science 282 :1497– 1501.
57. 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 :42462– 42467.
58. 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 :5214– 5222.
59. Buschmann, T.,, O. Potapova,, A. Bar-Shira,, V. N. Ivanov,, S. Y. Fuchs,, S. Henderson,, V. A. Fried,, T. Minamoto,, D. Alarcon-Vargas,, M. R. Pincus,, W. A. Gaarde,, N. J. Holbrook,, Y. Shiloh, and, Z. Ronai. 2001. Jun NH 2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress. Mol. Cell. Biol. 21 :2743– 2754.
60. Busino, L.,, M. Donzelli,, M. Chiesa,, D. Guardavaccaro,, D. Gan-oth,, N. V. Dorrello,, A. Hershko,, M. Pagano, and, G. F. Draetta. 2003. Degradation of Cdc25A by (3-TrCP during S phase and in response to DNA damage. Nature 426 :87– 91.
61. Canman, C. E.,, D.-S. Lim,, K. A. Cimprich,, Y. Taya,, K. Tamai,, K. Sakaguchi,, E. Appella,, M. B. Kastan, and, J. D. Siciliano. 1998. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281 :1677– 1679.
62. Canman, C. E.,, A. C. Wolff,, C.-Y. Chen,, A. J. Fornace, Jr., and, M. B. Kastan. 1994. The p53-dependent G 1 cell cycle checkpoint pathway and ataxia-telangiectasia. Cancer Res. 54 :5054– 5058.
63. Capasso, H.,, C. Palermo,, S. Wan,, H. Rao,, U. P. John,, M. J. O’Connell, and, N. C. Walworth. 2002. Phosphorylation activates Chk1 and is required for checkpoint-mediated cell cycle arrest. J. Cell Sci. 115 :4555– 4564.
64. Carrier, F.,, P. T. Georgel,, P. Pourquier,, M. Blake,, H. U. Kontny,, M. J. Antinore,, M. Gariboldi,, T. G. Myers,, J. N. Weinstein,, Y. Pommier, and, A. J. Fornace, Jr., 1999. Gadd45, a p53-reponsive stress protein, modifies DNA accessibility on damaged chromatin. Mol. Cell. Biol. 19 :1673– 1685.
65. Carty, M. P.,, M. Zernik-Kobak,, S. McGrath, and, K. Dixon. 1994. UV light-induced DNA synthesis arrest in HeLa cells is associated with changes in phosphorylation of human single-stranded DNA-binding protein. EMBO J. 13 :2114– 2123.
66. Casper, A. M.,, P. Nghiem,, M. F. Arlt, and, T. W. Glover. 2002. ATR regulates fragile site stability. Cell 111 :779– 789.
67. Celeste, A.,, S. Petersen,, P. J. Romanienko,, O. Fernandez-Capetillo,, H. T. Chen,, O. A. Sedelnikova,, B. Reina-San-Martin,, V. Coppola,, E. Meffre,, M. J. Difilippantonio,, C. Redon,, D. R. Pilch,, A. Olaru,, M. Eckhaus,, R. D. Camerini-Otero,, L. Tessarollo,, F. Livak,, K. Manova,, W. M. Bonner,, M. C. Nussenzweig, and, A. Nussenzweig. 2002. Genomic instability in mice lacking histone H2AX. Science 296 :922– 927.
68. Cha, R. S., and, N. Kleckner. 2002. ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones. Science 297 :602– 606.
69. Chan, T. A.,, H. Hermeking,, C. Lengauer,, K. W. Kinzler, and, B. Vogelstein. 1999. 14–3-3σ is required to prevent mitotic catastrophe after DNA damage. Nature 401 :616– 620.
70. Chan, T. A.,, P. M. Hwang,, H. Hermeking,, K. W. Kinzler, and, B. Vogelstein. 2000. Cooperative effects of genes controlling the G 2/M checkpoint. Genes Dev. 14 :1584– 1588.
71. Chang, T. H. T.,, F. A. Ray,, D. A. Thompson, and, R. Schlegel. 1997. Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T-antigen in diploid human cells. Oncogene 14 :2383– 2393.
72. Chao, C.,, S. Saito,, C. W. Anderson,, E. Appella, and, Y. Xu. 2000. Phosphorylation of murine p53 at Ser-18 regulates the p53 responses to DNA damage. Proc. Natl. Acad. Sci. USA 97 :11936– 11941.
73. Chaturvedi, P.,, W. K. Eng,, Y. Zhu,, M. R. Mattern,, R. Mishra,, M. R. Hurle,, X. Zhang,, R. S. Annan,, Q. Lu,, L. F. Faucette,, G. F. Scott,, X. Li,, S. A. Carr,, R. K. Johnson,, J. D. Winkler, and, B.-B. S. Zhou. 1999. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene 18 :4047– 4054.
74. Chehab, N. H.,, A. Malikzay,, M. Appel, and, T. D. Halazonetis. 2000. Chk2/hCds1 functions as a DNA damage checkpoint in G1 stabilizing p53. Genes Dev. 14 :278– 288.
75. Chehab, N. H.,, A. Malikzay,, E. S. Stavridi, and, T. D. Halazonetis. 1999. Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc. Natl. Acad. Sci. USA 96 :13777– 13782.
76. Chen, C.-Y.,, J. D. Oliner,, Q. Zhan,, A. J. Fornace, Jr.,, B. Vogelstein, and, M. B. Kastan. 1994. Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway. Proc. Natl. Acad. Sci. USA 91 :2684– 2688.
77. Chen, J.,, P. K. Jackson,, M. W. Kirschner, and, A. Dutta. 1995. Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA. Nature 374 :386– 388.
78. Chen, Y., and, Y. Sanchez. 2004. Chk1 in the DNA damage response: conserved roles from yeasts to mammals. DNA Repair 3 :1025– 1032.
79. Chernov, M. V.,, C. V. Ramana,, V. V. Adler, and, G. R. Stark. 1998. Stabilization and activation of p53 are regulated independently by different phosphorylation events. Proc. Natl. Acad. Sci. USA 95 :2284– 2289.
80. Chini, C., and, J. Chen. 2004. Claspin, a regulator of Chk1 in replication stress pathway. DNA Repair 3 :1033– 1037.
81. Chini, C., and, J. Chen. 2003. Human claspin is required for replication checkpoint control. J. Biol. Chem. 278 :30057– 30062.
82. Cohen-Fix, O., and, D. Koshland. 1997. The anaphase inhibitor of Saccharomyces cerevisiae Pds1p is a target of the DNA damage checkpoint pathway. Proc. Natl. Acad. Sci. USA 94 :14361– 14366.
83. Cohen-Fix, O., and, D. Koshland. 1997. The metaphase-to-anaphase transition: avoiding a mid-life crisis. Curr. Opin. Cell Biol. 9 :800– 806.
84. Cortez, D.,, G. Glick, and, S. J. Elledge. 2004. Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Proc. Natl. Acad. Sci. USA 101 :10078– 10083.
85. Cortez, D.,, Y. Wang,, J. Qin, and, S. J. Elledge. 1999. Requirement of ATM-dependent phosphorylation of Brca1 in the DNA damage response to double-strand breaks. Science 286 :1162– 1166.
86. Costanzo, V.,, K. Robertson,, C. Y. Ying,, E. Kim,, E. Avvedimento,, M. Gottesman,, D. Grieco, and, J. Gautier. 2000. Reconstitution of an ATM-dependent checkpoint that inhibits chromosomal DNA replication following DNA damage. Mol. Cell 6 :649– 659.
87. Costanzo, V.,, D. Shechter,, P. J. Lupardus,, K. A. Cimprich,, M. Gottesman, and, J. Gautier. 2003. An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. Mol. Cell 11 :203– 213.
88. de la Torre-Ruiz, M.-A., and, N. F. Lowndes. 2000. The Saccha-romyces cerevisiae DNA damage checkpoint is required for efficient repair of double strand breaks by non-homologous end joining. FEBS Lett. 467 :311– 315.
89. Demers, G. W.,, S. A. Foster,, C. L. Halbert, and, D. A. Galloway. 1994. Growth arrest by induction of p53 in DNA damaged keratinocytes is bypassed by human papillomavirus 16 E7. Proc. Natl. Acad. Sci. USA 91 : 4382– 4386.
90. Deng, C.,, P. Zhang,, J. W. Harper,, S. J. Elledge, and, P. Leder. 1995. Mice lacking p21 CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82 :675– 684.
91. Deng, C.-X., and, S. G. Brodie. 2000. Roles of BRCA1 and its interacting proteins. Bioessays 22 :728– 737.
92. Deng, J.,, H. P. Harding,, B. Raught,, A.-C. Gingras,, J. J. Berlanga,, D. Scheuner,, R. J. Kaufman,, D. Ron, and, N. Sonenberg. 2002. Activation of GCN2 in UV-irradiated cells inhibits translation. Curr. Biol. 12 :1279– 1286.
93. DiTullio, R. A., Jr.,, T. A. Mochan,, M. Venere,, J. Bartkova,, M. Se-hested,, J. Bartek, and, T. D. Halazonetis. 2003. 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer. Nat. Cell Biol. 4 :998– 1002.
94. D’Orazi, G.,, B. Cecchinelli,, T. Bruno,, I. Manni,, Y. Higashimoto,, S. Saito,, M. Gostissa,, S. Coen,, A. Marchetti,, G. Del Sal,, G. Piaggio,, M. Fanciulli,, E. Appella, and, S. Soddu. 2002. Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nat. Cell Biol. 4 :11– 19.
95. Dornan, D.,, H. Shimizu,, N. D. Perkins, and, T. R. Hupp. 2003. DNA-dependent acetylation of p53 by the transcription coactivator p300. J. Biol. Chem. 278 :13431– 13441.
96. Dornan, D.,, I. Wertz,, H. Shimizu,, D. Arnott,, G. D. Frantz,, P. Dowd,, K. O’Rourke,, H. Koeppen, and, V. M. Dixit. 2004. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 429 :86– 92.
97. Du, L. L.,, T. M. Nakamura,, B. A. Moser, and, P. Russell. 2003. Retention but not recruitment of Crb2 at double-strand breaks requires Rad1 and Rad3 complexes. Mol. Cell. Biol. 23 :6150– 6158.
98. Dulic, V.,, W. K. Kaufmann,, S. J. Wilson,, T. D. Tlsty,, E. Lees,, J. W. Harper,, S. J. Elledge, and, S. I. Reed. 1994. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 76 :1013– 1023.
99. Dulic, V.,, G. H. Stein,, D. F. Far, and, S. I. Reed. 1998. Nuclear accumulation of p21 Cip1 at the onset of mitosis: a role at the G2/M transition. Mol. Cell. Biol. 18 :546– 557.
100. Dumaz, N., and, D. W. Meek. 1999. Serine15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2. EMBO J. 18 :7002– 7010.
101. Durocher, D.,, J. Henckel,, A. R. Fersht, and, S. P. Jackson. 1999. The FHA domain is a modular phosphopeptide recognition motif. Mol. Cell 4 :387– 394.
102. Dutta, A.,, J. M. Ruppert,, J. C. Aster, and, E. Winchester. 1993. Inhibition of DNA replication factor RPA by p53. Nature 365 :79– 82.
103. Dutta, A., and, B. Stillman. 1992. Cdc2 family kinases phosphorylate a human cell DNA replication factor, RPA, and activate DNA replication. EMBO J. 6 :2189– 2199.
104. El-Deiry, W. S.,, J. W. Harper,, P. M. O’Connor,, V. E. Velculescu,, C. E. Canman,, J. Jackman,, J. A. Pietenpol,, M. Burrell,, D. E. Hill,, Y. Wang,, K. G. Wiman,, W. E. Mercer,, M. B. Kastan,, K. W. Kohn,, S. J. Elledge,, K. W. Kinzler, and, B. Vogelstein. 1994. WAF1/CIP1 is induced in pS3-mediated G 1 arrest and apoptosis. Cancer Res. 54 :1169– 1174.
105. El-Deiry, W. S.,, S. E. Kern,, J. A. Pietenpol,, K. W. Kinzler, and, B. Vogelstein. 1992. Human genomic DNA sequences define a consensus binding site for human p53 protein complexes. Nat. Genet. 1 :44– 49.
106. El-Deiry, W. S.,, T. Tokino,, V. E. Velculescu,, D. B. Levy,, R. Parsons,, J. M. Trent,, D. Lin,, W. E. Mercer,, K. W. Kinzler, and, B. Vogelstein. 1993. WAF1, a potential mediator of p53 tumor suppression. Cell 75 :817– 825.
107. Emili, A., 1998. Mec1-dependent phosphorylation of Rad9p in response to DNA damage. Mol. Cell 2 :183– 189.
108. Emili, A.,, D. M. Schieltz,, J. R. Yates III, and, L. H. Hartwell. 2001. Dynamic interaction of DNA damage checkpoint protein Rad53 with chromatin assembly factor Asf1. Mol. Cell 7 :13– 20.
109. Fabbro, M.,, K. Savage,, K. Hobson,, A. J. Deans,, S. N. Powell,, G. A. McArthur, and, K. K. Khanna. 2004. BRCA1-BARD1 complexes are required for p53 Ser-15 phosphorylation and a G 1/S arrest following ionizing radiation-induced DNA damage. J. Biol. Chem. 279 :31251– 31258.
110. Falck, J.,, N. Mailand,, R. G. Syljuåsen,, J. Bartek, and, J. Lukas. 2001.  The ATM-Chk2-Cdc25A checkpoint pathway guards against ra-dioresistant DNA synthesis. Nature 410 :842– 847.
111. Falck, J.,, J. H. J. Petrini,, B. R. Williams,, J. Lukas, and, J. Bartek. 2002.  The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nat. Genet. 30 :290– 294.
112. Feijoo, C.,, C. Hall-Jackson,, R. Wu,, D. Jenkins,, J. Leitch,, D. M. Gilbert, and, C. Smythe. 2001. Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. J. Cell Biol. 154 :913– 923.
113. Fernandez-Capetillo, O.,, H. T. Chen,, A. Celeste,, I. Ward,, P. J. Romanienko,, J. C. Morales,, K. Naka,, Z. Xia,, R. D. Camerini-Otero,, N. Motoyama,, P. B. Carpenter,, W. M. Bonner,, J. Chen, and, A. Nussen-zweig. 2002. DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat. Cell Biol. 4 :993– 997.
114. Fitz Gerald, J. N.,, J. M. Benjamin, and, S. J. Kron. 2002. Robust G1 checkpoint arrest in budding yeast: dependence on DNA damage signaling and repair. J. Cell Sci. 115 :1749– 1757.
115. Fogarty, P.,, S. D. Campbell,, R. Abu-Shumays,, B. Phalle,, K. Yu,, G. Uy,, M. Goldberg, and, W. Sullivan. 1997. The Drosophila grapes gene is related to checkpoint gene chk1/rad27 and is required for late syncytial division fidelity. Curr. Biol. 7 :418– 426.
116. Forbes, K. C.,, T. Humphrey, and, T. Enoch. 1998. Suppressors of Cdc25p overexpression identify two pathways that influence the G2/M checkpoint in fission yeast. Genetics 150 :1361– 1375.
117. Ford, J. C.,, F. Al-Khodairy,, E. Fotou,, K. S. Sheldrick,, D. J. F. Griffiths, and, A. M. Carr. 1994. 14–3-3 protein homologs required for the DNA damage checkpoint in fission yeast. Science 265 :533– 535.
118. Fornace, A. J., Jr.,, D. W. Nebert,, M. C. Hollander,, J. D. Luethy,, M. Papathanasiou,, J. Fargnoli, and, N. J. Holbrook. 1989. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol. Cell. Biol. 9 :4196– 4203.
119. Forrest, A., and, B. Gabrielli. 2001. Cdc25B activity is regulated by 14–3-3. Oncogene 20 :4393– 4401.
120. Foss, E. J., 2001. Tof1p regulates DNA damage responses during S phase in Saccharomyces cerevisiae. Genetics 157 :567– 577.
121. Francesconi, S.,, M. Grenon,, D. Bouvier, and, G. Baldacci. 1997. p56 chk1 protein kinase is required for the DNA replication checkpoint at 37°C in fission yeast. EMBO J. 16 :1332– 1341.
122. Freedman, D.,, L. Wu, and, A. Levine. 1999. Functions of the MDM2 oncoprotein. Cell. Mol. Life Sci. 55 :96– 107.
123. Fried, L. M.,, C. Koumenis,, S. Peterson,, S. L. Green,, P. van Zijl,, J. Allalunis-Turner,, D. J. Chen,, R. Fishel,, A. J. Giaccia,, J. M. Brown, and, C. U. Kirchgessner. 1996. The DNA damage response in DNA-dependent protein kinase-deficient SCID mouse cells: replication protein A hyper-phosphorylation and p53 induction. Proc. Natl. Acad. Sci. USA 93 :13825– 13830.
124. Furnari, B.,, A. Blasina,, M. N. Boddy,, C. H. McGowan, and, P. Russell. 1999. Cdc25 inhibited in vivo and in vitro by checkpoint kinases Cds1 and Chk1. Mol. Biol. Cell 10 :833– 845.
125. Furnari, B.,, N. Rhind, and, P. Russell. 1997. Cdc25 mitotic in-ducer targeted by Chk1 DNA damage checkpoint kinase. Science 277 :1495– 1497.
126. Gabrielli, B. G.,, J. M. Clark,, A. K. McCormack, and, K. A. O. Ellem. 1997. Ultraviolet light-induced G2 phase cell cycle checkpoint blocks cdc25-dependent progression into mitosis. Oncogene 15 :749– 758.
127. Gadbois, D. M., and, B. E. Lehnert. 1997. Temporal position of G 1 arrest in normal human fibroblasts after exposure to γ-rays. Exp. Cell Res. 232 :161– 166.
128. Gardner, R.,, C. W. Putnam, and, T. Weinert. 1999. RAD53, DUN1 and PDS1 define two parallel G 2/M checkpoint pathways in yeast. EMBO J. 18 :3173– 3185.
129. Gatei, M.,, K. Sloper,, C. Sorensen,, R. Syljuasen,, J. Falck,, K. Hobson,, K. Savage,, J. Lukas,, B. B. Zhou,, J. Bartek, and, K. K. Khanna. 2003. Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation. J. Biol. Chem. 278 :14806– 14811.
130. Giaccia, A. J., and, M. B. Kastan. 1998. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev. 12 :2973– 2983.
131. Gilbert, C. S.,, C. M. Green, and, N. F. Lowndes. 2001. Budding yeast Rad9 is an ATP-dependent Rad53 activating machine. Mol. Cell 8 :129– 136.
132. Glockzin, S.,, F. X. Ogi,, A. Hengstermann,, M. Scheffner, and, C. Blattner. 2003. Involvement of the DNA repair protein hHR23 in p53 degradation. Mol. Cell. Biol. 23 :8960– 8969.
133. Golding, S. E.,, E. Rosenberg,, A. Khalil,, A. McEwen,, M. Holmes,, S. Neill,, L. F. Povirk, and, K. Valerie. 2004. Double strand break repair by homologous recombination is regulated by cell cycle-independent signaling via ATM in human glioma cells. J. Biol. Chem. 279 :15402– 15410.
134. Gottifredi, V., and, C. Prives. 2001. Getting p53 out of the nucleus. Science 292 :1851– 1852.
135. Gottifredi, V.,, S.-Y. Shieh,, Y. Taya, and, C. Prives. 2001. p53 accumulates but is functionally impaired when DNA synthesis is blocked. Proc. Natl. Acad. Sci. USA 98 :1036– 1041.
136. Goudelock, D. M.,, K. Jiang,, E. Pereira,, B. Russell, and, Y. Sanchez. 2003. Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex. J. Biol. Chem. 278 :29940– 29947.
137. Groth, A.,, J. Lukas,, E. A. Nigg,, H. H. Sillje,, C. Wernstedt,, J. Bartek, and, K. Hansen. 2003. Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint. EMBO J. 22 :1676– 1687.
138. Gu, W., and, R. G. Roder. 1997. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90 :595– 606.
139. Gu, Y.,, C. W. Turck, and, D. O. Morgan. 1993. Inhibition of Cdk2 activity in vivo by an associated 20K regulatory subunit. Nature 366 :707– 710.
140. Guarente, L., 2000. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 14 :1021– 1026.
141. Guillouf, C.,, F. Rosselli,, K. Krishnaraju,, E. Moustacchi,, B. Hoffman, and, D. A. Liebermann. 1995. p53 involvement in control of G2 exit of the cell cycle: role in DNA damage-induced apoptosis. Oncogene 10 :2263– 2270.
142. Gulbis, J. M.,, Z. Kelman,, J. Hurwitz,, M. O’Donnell, and, J. Kuriyan. 1996. Structure of the C-terminal region of p21 WAF1/CIP1 com-plexed with human PCNA. Cell 87 :297– 306.
143. Guo, Z.,, A. Kumagai,, S. X. Wang, and, W. G. Dunphy. 2000. Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts. Genes Dev. 14 :2745– 2756.
144. Haapajarvi, T.,, K. Pitkanen,, M. Tsubari, and, M. Laiho. 1997. p53 transactivation and protein accumulation are independently regulated by UV light in different phases of the cell cycle. Mol. Cell. Biol. 17 :3074– 3080.
145. Hall, M.,, S. Bates, and, G. Peters. 1995. Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins. Oncogene 11 :1581– 1588.
146. Harkin, D. P.,, J. M. Bean,, D. Miklos,, Y. H. Song,, V. B. Truong,, C. Englert,, F. C. Christians,, L. W. Ellisen,, S. Maheswaran,, J. D. Oliner, and, D. A. Haber. 1999. Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97 :575– 586.
147. Harper, J. W.,, G. R. Adami,, N. Wei,, K. Keyomarsi, and, S. J. Elledge. 1993. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75 :805– 816.
148. Harper, J. W., and, S. J. Elledge. 1996. Cdk inhibitors in development and cancer. Curr. Opin. Genet. Dev. 6 :56– 64.
149. Harrington, E. A.,, J. L. Bruce,, E. Harlow, and, N. Dyson. 1998. pRB plays an essential role in cell cycle arrest induced by DNA damage. Proc. Natl. Acad. Sci. USA 95 :11945– 11950.
150. Haupt, Y.,, R. Maya,, A. Kazaz, and, M. Oren. 1997. Mdm2 promotes the rapid degradation of p53. Nature 387 :296– 299.
151. 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 :8552– 8561.
152. Hengst, L.,, V. Dulic,, J. M. Slingerland,, E. Lees, and, S. I. Reed. 1994. A cell cycle-regulated inhibitor of cyclin-dependent kinases. Proc. Natl. Acad. Sci. USA 91 :5291– 5295.
153. Hermeking, H.,, C. Lengauer,, K. Polyak,, T.-C. He,, L. Zhang,, S. Thiagalingam,, K. Kinzler, and, B. Vogelstein. 1997. 14–3-3σ is a p53-regulated inhibitor of G2/M progression. Mol. Cell 1 :3– 11.
154. Herzinger, T.,, J. O. Funk,, K. Hillmer,, D. Eick,, D. A. Wolf, and, P. Kind. 1995. Ultraviolet B irradiation-induced G2 cell cycle arrest in human keratinocytes by inhibitory phosphorylation of the cdc2 cell cycle kinase. Oncogene 11 :2151– 2156.
155. Higashimoto, Y.,, S. Saito,, X.-H. Tong,, A. Hong,, K. Sakaguchi,, E. Appella, and, C. W. Anderson. 2000. Human p53 is phosphorylated on serines 6 and 9 in response to DNA damage-inducing agents. J. Biol. Chem. 275 :23199– 23203.
156. Higashitani, A.,, H. Aoki,, A. Mori,, Y. Sasagawa,, T. Takanami, and, H. Takahashi., 2000. Caenorhabditis elegans Chk2-like gene is essential for meiosis but dispensable for DNA repair. FEBS Lett. 485 :35– 39.
157. Hirao, A.,, A. Cheung,, G. Duncan,, P.-M. Girard,, A. J. Elia,, A. Wakeham,, H. Okada,, T. Sarkissian,, J. A. Wong,, T. Sakai,, E. de Stanchina,, R. G. Bristow,, T. Suda,, S. W. Lowe,, P. Jeggo,, S. J. Elledge, and, T. W. Mak. 2002. Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and ATM-independent manner. Mol. Cell. Biol. 22 :6521– 6532.
158. Hirao, A.,, Y.-Y. Kong,, S. Matsuoka,, A. Wakeham,, J. Ruland,, H. Yoshida,, D. Liu,, S. J. Elledge, and, T. W. Mak. 2000. DNA damage- induced activation of p53 by the checkpoint kinase Chk2. Science 287 :1824– 1827.
159. Hirose, Y.,, M. S. Berger, and, R. O. Pieper. 2001. Abrogation of the Chk1-mediated G2 checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human glioblastoma cells. Cancer Res. 61 :5843– 5849.
160. Hofmann, T. G.,, A. Moller,, H. Sirma,, H. Zentgraf,, Y. Taya,, W. Droge,, H. Will, and, M. L. Schmitz. 2002. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nat. Cell Biol. 4 :1– 10.
161. Hollander, M. C., and, A. J. Fornace, Jr., 2002. Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a. Oncogene 21 :6228– 6233.
162. Hollander, M. C.,, M. S. Sheikh,, D. V. Bulavin,, K. Lundgren,, L. Augeri-Henmueller,, R. Shehee,, T. A. Molinaro,, K. E. Kim,, E. Tolosa,, J. D. Ashwell,, M. P. Rosenberg,, Q. Zhan,, P. M. Fernández-Salguero,, W. F. Morgan,, C.-X. Deng, and, A. J. Fornace, Jr., 1999. Genomic instability in Gadd45a-deficient mice. Nat. Genet. 23 :176– 184.
163. Hollstein, M.,, M. Hergenhahn,, Q. Yang,, H. Bartsch,, Z.-Q. Wang, and, P. Hainaut. 1999. New approaches to understanding p53 gene tumor mutations spectra. Mutat. Res. 431 :199– 209.
164. Hollstein, M.,, D. Sidransky,, B. Vogelstein, and, C. C. Harris. 1991. p53 mutations in human cancers. Science 253 :49– 53.
165. Hu, F.,, A. A. Alcasabas, and, S. J. Elledge. 2001. Asf1 links Rad53 to control of chromatin assembly. Genes Dev. 15 :1061– 1066.
166. Hu, F.,, Y. Wang,, D. Liu,, Y. Li,, J. Qin, and, S. J. Elledge. 2001. Regulation of the Bub2/Bfa1 GAP complex by Cdc5 and cell cycle checkpoints. Cell 107 :655– 665.
167. Huang, P., 1998. Excision of mismatched nucleotides from DNA: a potential mechanism for enhancing DNA replication fidelity by the wild-type p53 protein. Oncogene 17 :261– 270.
168. Hupp, T. R.,, D. W. Meek,, C. Midgley, and, D. Lane. 1992. Regulation of the specific DNA binding function of p53. Cell 71 :875– 886.
169. Ito, A.,, Y. Kawaguchi,, C. H. Lai,, J. J. Kovacs,, Y. Higashimoto,, E. Appella, and, T. P. Yao. 2002. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J. 21 :6236– 6245.
170. Iwabuchi, K.,, P. L. Bartel,, B. Li,, R. Marraccino, and, S. Fields. 1994. Two cellular proteins that bind to wild-type but not mutant p53. Proc. Natl. Acad. Sci. USA 91 :6098– 6102.
171. Jack, M. T.,, R. A. Woo,, A. Hirao,, A. Cheung,, T. W. Mak, and, P. W. K. Lee. 2002. Chk2 is dispensable for p53-mediated G 1 arrest but is required for a latent p53-mediated apoptotic response. Proc. Natl. Acad. Sci. USA 99 :9825– 9829.
172. Jackson, M. W., and, S. J. Berberich. 2000. MdmX protects p53 from Mdm2-mediated degradation. Mol. Cell. Biol. 20 :1001– 1007.
173. Jackson, P. K., 2004. Linking tumor suppression, DNA damage and the anaphase-promoting complex. Trends Cell Biol. 14 :331– 334.
174. Janz, C., and, L. Wiesmüller. 2002. Wild-type p53 inhibits replication-associated homologous recombination. Oncogene 21 :5929– 5933.
175. Jayaraman, L.,, N. C. Moorthy,, K. G. K. Murthy,, J. L. Manley,, M. Bustin, and, C. Prives. 1998. High mobility group protein-1 (HMG-1) is a unique activator of p53. Genes Dev. 12 :462– 472.
176. Jayaraman, L.,, K. G. K. Murthy,, C. Zhu,, T. Curran,, S. Xan-thoudakis, and, C. Prives. 1997. Identification of redox/repair protein Ref-1 as a potent activator of p53. Genes Dev. 11 :558– 570.
177. Jayaraman, L., and, C. Prives. 1995. Activation of p53 sequence-specific DNA binding by short single strands of DNA requires the p53 C-terminus. Cell 81 :1021– 1029.
178. Jessberger, R., and, P. Berg. 1991. Repair of deletions and double-strand gaps by homologous recombination in a mammalian in vitro system. Mol. Cell. Biol. 11 :445– 457.
179. Jessberger, R.,, V. Podust,, U. Hübscher, and, P. Berg. 1993. A mammalian protein complex that repairs double-strand breaks and deletions by recombination. J. Biol. Chem. 268 :15070– 15079.
180. Jessberger, R.,, B. Riwar,, H. Baechtold, and, A. T. Akhmedov. 1996. SMC proteins constitute two subunits of the mammalian recombination complex RC-1. EMBO J 15 :4061– 4068.
181. Jin, P.,, Y. Gu, and, D. O. Morgan. 1996. Role of inhibitory CDC2 phosphorylation in radiation-induced G2 arrest in human cells. J. Cell Biol. 134 :963– 970.
182. Jin, S.,, M. J. Antinore,, F.-D. T. Lung,, X. Dong,, H. Zhao,, F. Fan,, A. B. Colchagie,, P. Blanck,, P. P. Roller,, A. J. Fornace, Jr., and, Q. Zhan. 2000. The GADD45 inhibition of Cdc2 kinase correlates with GADD45- mediated growth suppression. J. Biol. Chem. 275 :16602– 16608.
183. Jin, S.,, L. Mazzacurati,, X. Zhu,, T. Tong,, Y. Song,, S. Shujuan,, K. Petrik,, B. Rajasekaran,, M. Wu, and, Q. Zhan. 2003. Gadd45a contributes to p53 stabilization in response to DNA damage. Oncogene 22 :8536– 8540.
184. Jin, Y.,, S. X. Zeng,, M. S. Dai,, X. J. Yang, and, H. Lu. 2002. MDM2 inhibits PCAF (p300/CREB-binding protein-associated factor)- mediated p53 acetylation. J. Biol. Chem. 277 :30838– 30843.
185. Juven, T.,, Y. Barak,, A. Zauberman,, D. L. George, and, M. Oren. 1993. Wild type p53 can mediate sequence-specific transactivation of an internal promoter within the mdm2 gene. Oncogene 8 :3411– 3416.
186. Kai, M., and, T. S. Wang. 2003. Checkpoint activation regulates mutagenic translesion synthesis. Genes Dev. 17 :64– 76.
187. Kao, G. D.,, W. G. McKenna, and, T. J. Yen. 2001. Detection of repair activity during DNA damage-induced G2 delay in human cancer cells. Oncogene 20 :3486– 3496.
188. Kaplun, L.,, Y. Ivantsiv,, D. Kornitzer, and, D. Raveh. 2000. Functions of the DNA damage response pathway target HO endonuclease of yeast for degradation via the ubiquitin-26S proteasome system. Proc. Natl. Acad. Sci. USA 97 :10077– 10082.
189. Kapoor, M., and, G. Lozano. 1998. Functional activation of p53 via phosphorylation following DNA damage by UV but not γ- radiation. Proc. Natl. Acad. Sci. USA 95 :2834– 2837.
190. 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 :6304– 6311.
191. 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 :587– 597.
192. Katou, Y.,, Y. Kanoh,, M. Bando,, H. Noguchi,, H. Tanaka,, T. Ashikari,, K. Sugimoto, and, K. Shirahige. 2003. S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature 424 :1078– 1083.
193. Katsuragi, Y., and, N. Sagata. 2004. Regulation of Chk1 kinase by autoinhibition and ATR-mediated phosphorylation. Mol. Biol. Cell 15 :1680– 1689.
194. Keller, D. M.,, X. Zeng,, Y. Wang,, Q. H. Zhang,, M. Kapoor,, H. Shu,, R. Goodman,, G. Lozano,, Y. Zhao, and, H. Lu. 2001. A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1. Mol. Cell 7 :283– 292.
195. Khan, S. H.,, J. Moritsugu, and, G. M. Wahl. 2000. Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion. Proc. Natl. Acad. Sci. USA 97 :3266– 3271.
196. Khanna, K. K.,, K. E. Keating,, S. Kozlov,, S. Scott,, M. Gatei,, K. Hobson,, Y. Taya,, B. Gabrielli,, D. Chan,, S. P. Lees-Miller, and, M. F. Lavin. 1998. ATM associates with and phosphorylates p53: mapping the region of interaction. Nat. Genet. 20 :398– 400.
197. Khanna, K. K., and, M. F. Lavin. 1993. Ionizing radiation and UV induction of p53 protein by different pathways in ataxia-telangiectasia cells. Oncogene 8 :3411– 3416.
198. Kharbanda, S.,, R. Ren,, P. Pandey,, T. D. Shafman,, S. M. Feller,, R. R. Weichselbaum, and, D. W. Kufe. 1995. Activation of the c-Abl tyro-sine kinase in the stress response to DNA-damaging agents. Nature 376 :785– 788.
199. Khosravi, R.,, R. Maya,, T. Gottlieb,, M. Oren,, Y. Shiloh, and, D. Shkedy. 1999. Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc. Natl. Acad. Sci. USA 96 :14973– 14977.
200. Kim, S.-T.,, B. Xu, and, M. B. Kastan. 2002. Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. Genes Dev. 16 :560– 570.
201. Kitagawa, R.,, C. J. Bakkenist,, P. J. McKinnon, and, M. B. Kastan. 2004. Phosphorylation of SMC1 is a critical downstream event in the ATM-NBS1-BRCA1 pathway. Genes Dev. 18 :1423– 1438.
202. Ko, L. J., and, C. Prives. 1996. p53: puzzle and paradigm. Genes Dev. 10 :1054– 1072.
203. Ko, L. J.,, S. Y. Shieh,, X. Chen,, L. Jayaraman,, K. Tamai,, Y. Taya,, C. Prives, and, Z. Q. Pan. 1997. p53 is phosphorylated by CDK7-cyclin H in a p36MAT1-dependent manner. Mol. Cell. Biol. 17 :7220– 7229.
204. Kouzarides, T., 2000. Acetylation: a regulatory modification to rival phosphorylation? EMBO J. 19 :1176– 1179.
205. Kubbutat, M. H. G.,, S. N. Jones, and, K. H. Vousden. 1997. Regulation of p53 stability by Mdm2. Nature 387 :299– 303.
206. 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 :7491– 7495.
207. Kumagai, A., and, W. G. Dunphy. 2000. 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.
208. Kumagai, A.,, Z. Guo,, K. H. Emami,, S. X. Wang, and, W. G. Dunphy. 1998. The Xenopus Chk1 protein kinase mediates a caffeine-sensitive pathway of checkpoint control in cell-free extracts. J. Cell Biol. 142 : 1559– 1569.
209. Lakin, N. D.,, B. C. Hann, and, S. P. Jackson. 1999. The ataxiatelangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53. Oncogene 18 :3989– 3995.
210. Lakin, N. D., and, S. P. Jackson. 1999. Regulation of p53 in response to DNA damage. Oncogene 18 :7644– 7655.
211. Lambert, P. F.,, F. Kashanchi,, M. F. Radonovich,, R. Shiekhattar, and, J. N. Brady. 1998. Phosphorylation of p53 serine 15 increases interaction with CBP. J. Biol. Chem. 273 :33048– 33053.
212. Lane, D. P., and, L. V. Crawford. 1979. T antigen is bound to a host protein in SV40 transformed cells. Nature 278 :261– 263.
213. Langley, E.,, M. Pearson,, M. Faretta,, U.-M. Bauer,, R. A. Frye,, S. Minucci,, P. G. Pelicci, and, T. Kouzarides. 2002. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J. 21 :2383– 2396.
214. Lee, C.,, J.-S. Kim, and, T. Waldman. 2004. PTEN gene targeting reveals a radiation-induced size checkpoint in human cancer cells. Cancer Res. 64 :6906– 6914.