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Chapter 26 : Diseases Associated with Defective Responses to DNA Strand Breaks

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Abstract:

This chapter focuses on the clinical disorders associated with defective DNA strand break repair and the relationship between the defective genes and the phenotypes observed in patients and their cells, where the disorders are Ataxia Telangiectasia (AT) (Louis-Bar Syndrome), Nijmegen breakage syndrome (NBS), AT-like disorder (ATLD), DNA ligase IV mutations, seckel syndrome, severe combined immunodeficiency, and spinocerebellar ataxia with axonal neuropathy (SCAN1). Identification of the defective genes responsible for these disorders has proven to be extremely valuable in elucidating pathways for DNA strand break repair and, importantly, for cell cycle checkpoint mechanisms.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26

Key Concept Ranking

DNA Synthesis
0.62205744
Genetic Recombination
0.6069679
DNA Polymerase I
0.49389482
Small Interfering RNA
0.47201788
0.62205744
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Figures

Image of Figure 26–1
Figure 26–1

The major cause of mortality for patients with AT is not malignancy but rather pulmonary infection. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–2
Figure 26–2

Cells from individuals with AT are abnormally sensitive to killing by ionizing radiation.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–3
Figure 26–3

Radioresistant-DNA synthesis in AT cells exposed to ionizing radiation. Note that normal cells manifest an immediate rapid inhibition component in the presence of low doses of ionizing radiation, followed by a less dramatic inhibition in the presence of higher doses. The former component has been suggested to reflect the inhibition of replicon initiation and is sensitive to low doses of radiation because the target (a large replicon cluster) is relatively large. The less severe component of replication inhibition has been suggested to reflect the inhibition of DNA replication fork progression, which is a smaller target for damage. The observation that the (presumed) inhibition of fork progression occurs to about the same extent in AT cells and normal cells (indicated by the parallel slopes of the two curves) suggests that AT cells are primarily insensitive (resistant) to inhibition of the initiation of replication following exposure to ionizing radiation.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–4
Figure 26–4

Normal and AT heterozygote cells show an arrest in the G/M phase of the cell cycle when exposed to ionizing radiation. AT cells fail to show this cell cycle arrest.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–5
Figure 26–5

AT cells can be assigned to different genetic complementation groups on the basis of the ability of heterodikaryons to support the normalinhibition of DNA synthesis (radiosensitive DNA synthesis) after exposure to ionizing radiation. (A) Monokaryons from AT cells show reduced inhibition of (radioresistant) DNA synthesis relative to control cells. (B) Heterodikaryons (dikaryons) formed by fusing AT cells from different complementation groups show a normal inhibition response.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–6
Figure 26–6

Cumulative pace of disease gene discovery (1981 to 2003). (Adapted from the National Human Genome Research web site [www.genome.gov/].)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–7
Figure 26–7

Alignment of predicted protein products for the ATM family of protein kinases. For the ATM protein, the leucine zipper, PI3 kinase motifs, and helix-turn-helix (hth) motifs are indicated. For other members of the ATM family, regions of similarity to the ATM protein are indicated by different degrees of shading. a.a., amino acids. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–8
Figure 26–8

Spectra of mutations found in patients (based on data from the Ataxia Telangiectasia Database at "http:www.benaroyaresearch.org/investigators/concannon_patrick/atm.htm.) Only 33 (17%) of 196 reported mutations in AT patients code for in-frame missense changes in the coding sequence, compared to 29 (67%) of 43 mutations in sporadic tumors. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–9
Figure 26–9

Effects of 7636del9 mutation on survival following exposure to ionizing radiation. (A) Survival after exposure to increasing doses of radiation for human control cells (C3ABR), AT cells homozygous for the 7637del9 deletion (AT1ABR), and cells from the parents of AT1ABR (ATH1ABR and ATH2ABR), both heterozygous for the 7636del9 mutation. (B) Survival after exposure to increasing doses of radiation for mouse cells representing wild-type and Atm-ΔSRI homozygous and heterozygous genotypes. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–10
Figure 26–10

The R278H mutation impairs DNA ligase IV enzyme activities. (A) Whole-cell extracts (WCE) of 1BRneo (control) and 180BRneo (R278H mutant) cells were analyzed by Western blotting using antibodies against DNA ligase IV, and equal amounts of protein were detected. Immunoprecipitation (IP) was performed using anti-XRCC4 antibodies, which efficiently coimmunoprecipitate DNA ligase IV. Adenylation of DNA ligase IV was measured in the presence or absence of inorganic pyrophosphate (+ /-PP), the presence of which disrupts the prior enzyme-adenylate complex and facilitates the monitoring of new-complex formation. Mutant R278H ligase protein formed the AMP-ligase complex poorly. (B) Whole-cell extracts of 1BRneo or 180BRneo cells were immunoprecipitated, PP treated, and examined for ligase activity. A 33-mer was radiolabeled, and ligation produced a radiolabeled 50-mer product. Mutant (180BRneo) cell extracts were deficient in DNA ligase activity relative to control (1BRneo) extracts. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–11
Figure 26–11

Sensitivity of Seckel syndrome cells to ionizing radiation (A), mitomycin C (B) and UV radiation (C). The axis shows the percent survival. Results are shown for 1BR3 (control) and F02-98 (Seckel syndrome) cells and for 425BR cells, a characterized FA group A cell line, exposed to mitomycin C and for XP-18BR cells, an XP group A cell line, exposed to UV radiation. The F02-98 cells are more sensitive to mitomycin C and UV radiation than the normal cells, but not for ionizing radiation. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–12
Figure 26–12

Cells with siRNA inactivation of ATR have increased fragile-site expression. (A) Western blot probed with anti-ATR antibody shows reduced ATR expression in two different cell lines (HCT116 and HeLa), each transfected with two different siRNA constructs (siRNA1 or siRNA2). (B and C) Average overall chromosomal gaps and breaks in HeLa cells (B) or HCT116 cells (C) after transfection with siRNA1, siRNA2, or control RNAs (cRNA); = 20 metaphases for each condition. ATR was inactivated by siRNA transfection 48 h before harvest. Fragile-site induction was achieved by the addition of 0.3 μM aphidicolin (APH) 24 h before harvest. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–13
Figure 26–13

Cells from patients with SCKL1 have increased fragile-site expression. The average total chromosome gaps and breaks per cell is shown. Fragile-site induction was achieved by the addition of 0.4 mM aphidicolin (APH) 48 h before harvest. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–14
Figure 26–14

Increased fragile-site expression in cells from patients with SCKL1 occurs at common fragile sites. The percentage of hybridizations with a break was determined after hybridizing the slide with a fluorescently labeled probe for the common FRA3B site. Fragile-site induction was achieved by the addition of 0.4 mM aphidicolin (APH) 48 h before harvest. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–15
Figure 26–15

Model of the resolution of stalled covalent topoisomerase I-DNA complexes that result in single-stranded DNA breaks. A proteolysis enzyme partially digests topoisomerase I, which is covalently linked to DNA at the single-strand break. Subsequently, TDP1 catalyzes hydrolysis of the phosphodiester bond between the tyrosine residue and the DNA 3’ phosphate. PNKP removes the phosphate at the 3’ end and phosphorylates the 5’ end, yielding the common substrate for DNA ligation. It is interesting to note that PNKP interacts with DNA polymerase β, DNA ligase III, and XRCC1 to form the single-strand break repair complex. It has been suggested that aprataxin may function during single-stranded DNA repair, providing a link between SCAN1 and early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) and/or ataxia-ocular apraxia 1 (AOA1). “?” denotes effects that are as yet undefined. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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Image of Figure 26–16
Figure 26–16

TDP1 repairs 3’-phosphotyrosine linkages between DNA and stalled topoisomerase enzymes. (A) Human Tdp1 was crystallized with a synthetic peptide-oligonucleotide substrate mimicking the 3’-phosphotyrosine intermediate formed by topoisomerase I and a cleaved DNA during unwinding of supercoiled DNA. (B) Tdp1 cleaved the phosphotyrosine bond of the substrate analog used for crystallization. Mutational studies of active-site residues in conjunction with activity assays using native and cleavage-activated substrate mimics suggest that His263 is the nucleophile for cleavage of the phosphotyrosine bond and His493 protonates the tyrosine leaving group. Other catalytically important residues are labeled.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Defective Responses to DNA Strand Breaks, p 919-946. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch26
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