Chapter 28 : Additional Diseases Associated with Defective Responses to DNA Damage

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This chapter examines two genetic disorders, each exhibiting locus heterogeneity and each representing the biological consequences of mutations in different genes in a specific DNA repair pathway. Both of these disorders present with a significant cancer predisposition and have associated cellular characteristics reflective of inherent chromosome instability. However, experimental approaches to the identification and characterization of the underlying genetics have taken strikingly different paths. The first of these disorders, hereditary nonpolyposis colon cancer (HNPCC), results from mutations in different genes associated with DNA mismatch repair (MMR). Given that MMR had been extensively studied before its connection to HNPCC was established, more recent studies have focused on evaluating additional MMR candidate genes for mutations in patients with HNPCC and elucidation of the biological basis for the organ-specific nature of the disorder. In contrast, the second disease considered in this chapter, is a disorder represented by multiple complementation groups that all exhibit defects in cross-link repair and responses to oxidative damage. These are not repair functions that are well defined or representative of established biochemical pathways. Therefore, experimental approaches have focused on the identification of the different genes responsible for FA and characterization of how the proteins involved define a unique biological pathway.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Additional Diseases Associated with Defective Responses to DNA Damage, p 979-999. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch28

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Tumor Necrosis Factor alpha
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Image of Figure 28–1
Figure 28–1

An extended pedigree consistent with a diagnosis of HNPCC brought to light following cancer diagnosis in the proband (arrow). Squares denote males and circles denote females, with a slash to identify deceased family members. Age at death (d) is given below each patient who died, with Inf indicating infancy. Open symbols are unaffected family members, while bicolored symbols identify individuals with multiple primary cancers. Squares or circles with numbers denote the number of unaffected male or female progeny, and combined symbols containing numbers denote the number of unaffected progeny of both sexes. Primary cancer and the age at diagnosis are shown below the symbols, and the bottom-most number is the current age or the age at death.(Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Additional Diseases Associated with Defective Responses to DNA Damage, p 979-999. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch28
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Image of Figure 28–2
Figure 28–2

DNA polymerase slippage. Depicted are both the normal replication product and the result of strand slippage following a second round of DNA replication. (Adapted from http://www.nottingham.ac.uk/microbiology/.)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Additional Diseases Associated with Defective Responses to DNA Damage, p 979-999. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch28
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Image of Figure 28–3
Figure 28–3

H6 cells are defective in the repair of (GT)•(CA) and (GT)•(CA) heteroduplexes. (GT)•(CA) and (GT)•(CA) heteroduplexes and (GT)•(CA) and (GT)•(CA) homoduplexes were subjected to MMR by nuclear extracts of H6 cells (see the text) and of SO cells (see the text). BLNK indicates no extract. Strand specificity was provided by incision of the complementary or viral strands at Sau961 or gpII sites, respectively. After the reaction, the repeated sequence elements were excised from the reaction products by cleavage at flanking restriction enzyme sites and then separated by electrophoresis. The products were visualized by hybridization with strand-specific probes.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Additional Diseases Associated with Defective Responses to DNA Damage, p 979-999. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch28
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Image of Figure 28–4
Figure 28–4

Putative role of mutations in MMR genes. A mutation in one MMR gene leads to reduced MMR function due to haploinsufficiency, which promotes mutations in traditional genes, such as the adenomatous polyposis coli gene and K Genes with coding microsatellites accumulate frameshift mutations and lose function, leading to cancer. The target genes likely dictate the organ specificity of HNPCC. The approximate percentages of all colorectal cancers with MMR deficiency that harbor these frameshift mutations are shown at the top. The three MMR genes that have coding microsatellites are shown at the bottom. β denotes transforming growth factor β1 receptor II, denotes retinoblastoma protein-interacting zinc finger, denotes transcription factor 4, denotes BCL-2-associated X, denotes insulin-like growth factor II receptor, and denotes deleted in colorectal cancer. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Additional Diseases Associated with Defective Responses to DNA Damage, p 979-999. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch28
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Image of Figure 28–5
Figure 28–5

FA cell sensitivity. (A) Cells from patients with FA are typically hypersensitive to treatment with agents such as mitomycin (MMC) that result in the formation of interstrand crosslinks in DNA. (B) Cells from certain FA genetic complementation groups also show a defect in the removal of cross-links from DNA.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Additional Diseases Associated with Defective Responses to DNA Damage, p 979-999. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch28
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Image of Figure 28–6
Figure 28–6

FA cells from genetic complementation group A (B) are defective in the recovery of normal rates of semiconservative DNA synthesis after exposure to psoralen plus 365-nm radiation. Normal cells and FA cells from genetic complementation group B are shown in panels A and C, respectively.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Additional Diseases Associated with Defective Responses to DNA Damage, p 979-999. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch28
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Figure 28–7

Homozygosity mapping of the FANCG gene. Homozygosity mapping of 269 microsatellite markers spaced at 11-cM intervals in an FA family is shown. Each box represents a microsatellite marker located on the 22 autosomes identified by number; gold boxes indicate markers that were informative and homozygous in both affected children, a result that would be consistent with linkage; shaded boxes indicate markers that were homozygous in both affected children but not informative; white boxes indicate markers that were heterozygous in at least one of the two affected children; missing boxes indicate markers that were not analyzed. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Additional Diseases Associated with Defective Responses to DNA Damage, p 979-999. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch28
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Figure 28–8

The FA-BRCA pathway. Several FA proteins, including A, B, C, E, F, G, and L, form a complex in the nuclei of normal human cells. In response to DNA damage, or during the S phase of the cell cycle, this complex mediates the monoubiquitination (Ub) of FANCD2 atlysine 561 (K561). Activated FANCD2, in turn, is translocated to chromatin and DNA repair foci containing the BRCA1 protein and the BRCA2-FANCD1 protein complex.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Additional Diseases Associated with Defective Responses to DNA Damage, p 979-999. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch28
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Table 28–1

Amsterdam criteria I and II

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Additional Diseases Associated with Defective Responses to DNA Damage, p 979-999. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch28