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Chapter 29 : Hereditary Diseases That Implicate Defective Responses to DNA Damage

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Abstract:

This chapter considers a number of human disorders that manifest clinical and/or cellular phenotypes suggestive of a relationship to defective DNA repair. Some of the disorders discussed in this chapter play well-documented and broad roles in DNA repair and/or DNA damage responses (e.g., p53 mutations in Li-Fraumeni syndrome patients). Others only exhibit phenotypes such as hypersensitivity to DNA-damaging agents, with no documented defects in the cellular responses to such agents (e.g., Roberts syndrome). The chapter is divided into three sections, covering hereditary cancer predispositions, disorders with documented alterations in chromatin structure, and relationships between aging and DNA repair.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29

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Mitogen-Activated Protein Kinase Pathway
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DNA Synthesis
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Transforming Growth Factor beta
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Image of Figure 29–1
Figure 29–1

Model for the regulation of DNA methylation. In normal cells, DNMT1 is regulated by RB1, and so maintenance methylation is carried out only at the hemimethylated CGs (the filled lollipop indicates methylcytosine) during replication, and excess DNMT1 is sequestered by RB1. Cancer cells lacking functional RB1 exhibit aberrant DNA methylation. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–2
Figure 29–2

Pedigree for a family with LFS. The index case (arrow) was diagnosed with sarcoma at age 20 and breast cancer at age 42. Tumors with uncertain clinical diagnoses are indicated by question marks. The pedigree illustrates the diversity of cancers seen in LFS families. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–3
Figure 29–3

Typical pedigree for a family exhibiting predisposition to breast cancer. Numbers indicate age at diagnosis. DNA analysis should focus on affected individuals since the failure to detect a mutation in the index case (arrow) could reflect either (i) no familial predisposition, (ii) the existence of a mutation difficult to detect (e.g., promoter region), or (iii) a mutation in an as yet unidentified breast cancer gene. Subsequent DNA analysis of affected individuals in this family identified a mutation in the gene. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–4
Figure 29–4

and gene structure and mutations. Numbered boxes denote exons. Arrows show the positions of mutations prevalent in the Ashkenazi Jewish population. Horizontal bars identify the difference in scale between the two genes. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–5
Figure 29–5

Functional domains of the APC protein. Asterisks indicate SAMP repeats of axin-binding sites. Arrows labeled A mark active nuclear export signals; arrows labeled B indicate sites of nuclear localization signals; arrows labeled C mark the positions of putative DNA-binding sequences. The arrow labeled D indicates the PTP-BL-binding site. Note that the 3’ end of the MCR falls before the first axin-binding site. Shown below is an association between the FAP phenotype and the position of the APC mutation. The gold area indicates the region of mutation in the associated FAP phenotype. aa, amino acid. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–6
Figure 29–6

The PTT. The coding region of a gene is screened for translation-terminating mutations by using in vitro protein synthesis from an amplified copy. Genomic DNA or RNA is isolated and amplified for the target gene coding sequences. The products are used as a template for the in vitro synthesis of RNA, which is subsequently translated into protein. The shorter protein products of mutated alleles are distinguished from the full-length protein products of normal alleles by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the synthesized protein. dsDNA, double-stranded DNA. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–7
Figure 29–7

Schematic of monoallelic mutation analysis. The hamster cell line UCW-56 is fused to an FAP lymphoblastoid line. Clones are subsequently selected at 39°C, as only clones that retain human chromosome 5, the chromosome where the APC gene maps, can grow at this temperature. Hybrids will retain at least one human chromosome 5, and most lose the second copy. Genotyping reveals which chromosome 5 is retained. Proteins from the fusion clones are analyzed by Western blotting with antibodies to both the amino and carboxyl ends of the APC protein. The N-terminal antibody (Human/rodent APC) reacts with human and rodent APC protein while the C-terminal antibody (Human APC) reacts only with human APC. Analysis of different clones is used to determine whether full-length APC expression occurs off each chromosome 5. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–8
Figure 29–8

Model of the genetic changes accumulating during the progression from adenoma to carcinoma in the development of colorectal cancer. The proposed order of mutations in APC, K-ras, p53, and the DNA mismatch repair (MMR) genes is illustrated. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–9
Figure 29–9

Role of APC in chromosome segregation. (A) Protein complexes at the plus ends of microtubules are adaptors that attach spindle microtubules to the kinetochores of chromosomes. In yeast, the Bim1/Kar9 protein complex connects microtubules to actin-rich structures in the daughter cell. (B) (Min) mutant ES cells exhibit significantly greater chromosome instability than wild-type controls (WT). Cell lines were established and propagated for 10 passages, and the number of autosomes in metaphase preparations was counted. (Adapted from references and .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–10
Figure 29–10

Evolutionary conservation of the variant residues in (A) Comparison of the variant residues Tyr165Cys (top) and Gly382Asp (bottom) identified in family N in with homologs from serovar Typhimurium ), and Arrows indicate the position of the variant residues. Identical, conserved, and semiconserved residues are shaded grey, light gold, and gold, respectively. // indicates the position of 18 amino acids in that are not present in the other organisms. (B) Results of single-turnover adenine glycosylase assays when wild-type, Y82C, and G253D MUTY proteins were assayed for glycosylase activity on a duplex substrate containing an 8-oxoG:A mismatch. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–11
Figure 29–11

Alternative origins for adenocarcinomas (Adenoca.). Sporadic tumors (A) arise from normal tissue, whereas a defect in a gatekeeper gene (B) would give rise to excess cell division and expansion of stromal tissue prior to progression to adenocarcinoma. A defect in a landscaper gene (C) would yield abnormal tissue organization and a microenvironment that could favor progression to adenocarcinoma. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–12
Figure 29–12

C-terminal STK11 mutants found in human cancer. The 12 different mutations of STK11 identified so far that affect only the C-terminal noncatalytic domain of STK11 are illustrated. The locations of the key phosphorylation sites are indicated by arrows. Asterisks denote numbering based on mouse STK11 sequence. The numbering of the mutations found in human cancers is based on the human sequences. NRD, N-terminal regulatory domain; CRD, C-terminal regulatory domain. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–13
Figure 29–13

Distribution of the different PTCH2 mutations found in the germ line in BCNS and in basal cell carcinoma from XP and non-XP repair-proficient patients. DEL, deletion; INS, insertion. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–14
Figure 29–14

Simplified view of sonic hedgehog, patched, and smoothened interactions. (A) Normally, patched (PTCH) inhibits smoothened (SMO) in the absence of sonic hedgehog (SHH). When SHH binds to PTCH, SMO is activated. (B) The hedgehog pathway will escape normal control via mutations in PTCH, leading to loss of inhibition of SMO or mutations in SMO leading to constitutive transcription. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–15
Figure 29–15

Regulation of the G/S transition by the Cdk4/6-cyclin D/INK4/Rb pathway. Progression through the G phase of the cell cycle is controlled by the functional state of the Rb family of proteins, RB1, p107, and p130. In G, Rb proteins are nonphosphorylated, a state that permits binding to the E2F family of transcription factors, preventing E2F-dependent transcription. In G, Cdk4 and/or Cdk6 kinases are activated by their mitogen-controlled regulatory subunits, cyclins D1, D2, and D3. Phosphorylation of Rb proteins by Cdk4/6-cyclin D complexes leads to their partial inactivation, allowing transcription of E2F-controlled genes such as cyclin E1, which activates the downstream Cdk2 kinase. The activity of Cdk4/6 is negatively regulated by the INK4 family of cell cycle inhibitors by preventing cyclin D binding. Cdk4/6-cyclin D complexes may also activate Cdk2 by binding Cip/Kip proteins, preventing them from blocking Cdk2-cyclin E activity. Hyperphosphorylation of Rb proteins by Cdk2-cyclin E complexes is required for proper G/S transition and initiation of S phase. Thick arrows illustrate the effects of mutations in human cancer that result in decreased (downward arrows) or increased (upward arrows) activity of the G/S regulators. The position of the restriction (R) point within G is arbitrary. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–16
Figure 29–16

Comparison of heterochromatin repulsion in control (A) and RS metaphase (B) chromosomes with DA-4’6-diamidino-2-phenylindole(DAPI) staining. Gold boxes identify representative centromeres from the two cell lines. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–17
Figure 29–17

Sensitivity of both primary and TERT-immortalized cell lines to hygromycin B at the indicated doses, confirming that RS cells are more sensitive than control cell lines and the phenotype is retained in the TERT cells. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–18
Figure 29–18

Methylation changes in ATRX patients. (A) The ratio of methylated to total rDNA is greater in normal controls than in ATRX individuals. (B) The ratio of methylated to total DYZ2 repeats is greater in ATRX individuals than in normal controls. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–19
Figure 29–19

Comparison of the protein and RNA molecules in small nucleolar ribonucleoprotein (snoRNP) and telomerase RNP complexes. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–20
Figure 29–20

Depiction of the molecular and cellular end points of aging and cancer as influenced by DNA damage. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–21
Figure 29–21

Progeria cells demonstrate appropriate endogenous TERT activity as detected in the blood cells of a patient afflicted with HGPS. Fresh blood lymphocytes were either unstimulated or stimulated for 72 h, and telomerase activity was detected as an extension of a 36-bp substrate. Both the normal and the HGPS samples demonstrated activity equivalent to a positive tumor control (H1299). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–22
Figure 29–22

Telomerase activity (A) and telomere length (B) in the control and TERT-infected cells representing a normal control, RS, XP group E (XPE), and Werner syndrome. The tumor-derived cell line, H1299, serves as a positive control, and the lysis buffer serves as a negative control. For telomere length, the results show the typical smear characteristic of human telomeres, but telomeres are longer in cells that have been infected with TERT. Positions of molecular mass markers are indicated on the left side (in kilodaltons). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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Image of Figure 29–23
Figure 29–23

Life span of control and TERT-infected cells, with the results expressed in population doublings. All uninfected control cells eventually entered replicative senescence (S) after a cumulative number of population doublings between 30 and 60 for each cell line as indicated. All cells infected with the TERT vector grew indefinitely (indicated by arrows). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Hereditary Diseases That Implicate Defective Responses to DNA Damage, p 1001-1047. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch29
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