Chapter 20 : Cell Cycle Checkpoints

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

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

Key Concept Ranking

DNA Synthesis
Small Interfering RNA
DNA Damage
DNA Replication Inhibitors
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Image of Figure 20–1
Figure 20–1

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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