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Chapter 23 : DNA Damage and the Regulation of Cell Fate

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Abstract:

This chapter discusses decisions about long-term cell fate that is intimately connected with regulatory responses to DNA-damaging agents in eukaryotes. The cell may attempt cell cycle progression while damage persists, a process termed adaptation. The chapter first describes the adaptation process and cell cycle restart. Adaptation in budding yeast correlates with active silencing of downstream effector kinases. Then, it introduces extrinsic and intrinsic pathways of apoptosis. The impact of other DNA damage-responsive transcriptional pathways that counteract or cooperate with p53 on apoptosis is also considered. Next, it briefly examines the relationships between DNA damage and senescence. Certain critical players determining cell fate during senescence that are overlapping with DNA damage responses have been described. Differentiation is an insufficiently understood response to DNA damage and is most probably triggered by slowed replication. In , the filamentous differentiation induced under such conditions is dependent on a subset of the DNA damage/replication checkpoint proteins (Rad53 and Mec1). However, in mammalian cells a checkpoint-like reversible inhibition of differentiation has also been shown after treatment with various DNA-damaging agents. All of these responses are important in the context of cancer and especially cancer therapy, where DNA-damaging agents are routinely employed to attain preferential killing of cancer cells. The chapter addresses selected aspects of these phenomena in the DNA damage context.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23

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Image of Figure 23–1
Figure 23–1

Assessment systems for DNA damage in and its influence on the threshold for adaptation. Presence of the yeast Ku complex (Yku70, Yku80) at a DSB site diminishes the damage signal and enables adaptation. The likely reason is the reduced DNA degradation around the DSB and, as a consequence, reduced binding of RPA (consisting of Rfa1, Rfa2, and Rfa3) signaling the presence of single-stranded DNA. The binding of the RecA homolog Rad51 or of Srs2 helicase dampens the damage signal (and, consequently, mutants fail to adapt). The interaction of Rad51 with Rad52 is essential for this effect. The presence of Rad52 without Rad51 has the opposite effect, enhancing the damage signal and increasing the adaptation threshold.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
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Image of Figure 23–2
Figure 23–2

Genetic consequences of adaptation to ionizing radiation damage in (Top) Cells of a DSB repair-deficient but adaptation-competent diploid strain (left) and an adaptation-deficient derivative (right) were plated (100,000 versus 30,000 per plate) and treated with 30 Gy of γ-irradiation. As the result of adaptation, small, slow-growing colonies with chromosome aberrations arise in the adaptation-competent strain. (Bottom) Disomic haploid strains show enhanced spontaneous chromosome loss as a result of adaptation to spontaneous DSB. An extra copy of chromosome VII carries wild-type complementing an defect in an otherwise mutant cell. Loss of the additional chromosome results in loss of red pigmentation (loss is indicated by white sectors in grey area) (see Fig. 17–3). This is evident for the wild type (left) but much less so for the adaptation-deficient strain (right). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
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Image of Figure 23–3
Figure 23–3

Some landmarks of apoptosis. Activation of an apoptotic pathway results in rounding of an adherent cell, DNA condensation, and fragmentation. Finally, disintegration of the entire cell into membrane-bound vesicles (apoptotic bodies) occurs. These can be phagocytosed by macrophages. The schematized agarose gel demonstrates the appearance of a ladder of DNA fragments during progressing apoptosis, indicating nuclease attack in internucleosomal regions of chromatin. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
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Image of Figure 23–4
Figure 23–4

Pathways of apoptosis. (A) In this scheme for extrinsic triggering of apoptosis, FAS ligand-mediated multimer formation of the FAS receptor and downstream activation of caspase-8 by autocleavage is depicted. (B) Intrinsic activation of apoptosis involves the BCL-2 family members that effect cytochrome release from mitochondria. Binding of cytochrome to the adaptor protein APAF-1 leads to the assembly of the apoptosome and caspase-9 activation. Consequently, downstream-acting caspases are also activated. Release of additional mitochondrial factors (SMAC/DIABLO) counteracts the inhibitors of those caspases (inhibitors of apoptotic proteins [IAP]). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
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Image of Figure 23–5
Figure 23–5

Scheme of the various transcriptional and nontranscriptional roles of p53 contributing to apoptosis. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
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Image of Figure 23–6
Figure 23–6

Domain structure of p63, p73, p53, and its various alternative splicing products. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
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Image of Figure 23–7
Figure 23–7

H1 histone distribution following IR treatment. (A) Histone H1 species are detected by Western blotting in the cytoplasmic extract fraction shown. An increased amount correlates with the fraction of apoptotic cells following IR exposure. (B) Detection of cytoplasmic dispersal of H1 histone following IR treatment by immunocytochemistry. NT, not treated. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
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Image of Figure 23–8
Figure 23–8

The response of human fibroblasts to senescence associated with telomere shortening is reminiscent of a DNA damage response (20 Gy of IR given to proliferating cells). Accumulation of 7H2AX and phosphorylated SMC1, RAD17, CHK1, and CHK2 proteins is measured using phosphospecific and phosphononspecific antibodies, as indicated to the right. The relevant protein bands are marked by asterisks if needed. For comparison, results with a comparable cell line forcibly expressing telomerase that had been grown for more generations than the senescent line are also shown (labeled “Proliferating telomerized”). Note that RAD17 also undergoes phosphorylation of Ser654 in S phase but in nondividing cells this phosphorylation is specific for senescent cells. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
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Image of Figure 23–9
Figure 23–9

Scheme for aging responses resulting in genetic instability triggered by telomere shortening. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
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Image of Figure 23–10
Figure 23–10

DNA damage-induced checkpoint arrest can protect from lethal effects of a drug whose effect is confined to mitosis. Wild-type cells and those deficient in p21 regulation were treated with the DNA-damaging agent doxorubicin. This drug causes mostly G arrest in HCT116 cells harboring wild-type p53 and thus having normal induction. Doxorubicin treatment protects from the lethal consequence of the microtubule drug paclitaxel (PTX, measured as loss in optical density of the culture [OD]) only if DNA damage checkpoint arrest is not compromised. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. DNA Damage and the Regulation of Cell Fate, p 845-862. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch23
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