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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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