Chapter 27 : Diseases Associated with Disordered DNA Helicase Function

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This chapter begins with a brief review of the biochemistry of RecQ helicases and is followed by a discussion of biological data obtained from the study of less complex organisms such as and yeast. The genomes of these organisms bear single gene homologs, and isolated mutants have provided insights into the general function of this family of proteins. The chapter then talks about human diseases that are characterized by defects in the human . The gene defective in was the first of the disease genes to be identified as a member of this human gene family. This was followed by identification of the gene mutated in . Analysis of two additional homologs, and , revealed gene mutations in some (but not all) patients with the cancer-prone human disorder and in patients with . In contrast to xeroderma pigmentosum, where mutations in any one of a number of different genes that function in nucleotide excision repair yield the same clinical phenotypes, the disorders described in the chapter exhibit distinct clinical and cellular features, suggesting that these similar proteins function at different stages of DNA metabolism. Each of the disorders is considered separately in the chapter, with a concluding summary of key similarities and differences.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–1
Figure 27–1

(A) The RecQ helicase has a claw-like structure consisting of two RecA-like domains of mixed α-β structure and a C-terminal α-helical region ( ). DNA-binding residues are located in the cleft between the RecA domains, and movements of these domains coupled to ATP hydrolysis power the separation of DNA strands by the helicase (compare Fig. 27–3 and 27-4 ). (B) The nucleotide-binding site of RecQ comprises residues on the edge of the central β-sheet within one of the RecA-like domains. These residues include Walker type I and II motifs, which are present in a wide variety of ATPases. A divalent metal ion (grey sphere) assists ATP hydrolysis, presumably by positioning the nucleotide and counteracting a buildup of negative charge on the γ-phosphate leaving group.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–2
Figure 27–2

The arginine finger and regulation of ATPase activity. The coupling of ATP hydrolysis with the DNA-unwinding activity of helicases involves a conformationally sensitive switch in ATPase activity mediated by a residue known as an arginine finger. (A) The Rep helicase binds ATP in the cleft between RecA-like domains ( )(compare Fig. 27–1 ). Most ATP-binding residues are located on one of the RecA domains, and a catalytically essential arginine (the arginine finger) is donated by the apposing RecA domain. An enlarged image of the dashed box is shown in (B). (B) Movements of the RecA domains in response to DNA binding and translocation are thought to position the arginine finger (Arg-finger) alternately in an active position contacting the γ-phosphate of ATP and an inactive conformation that allows ATP binding but not hydrolysis. In this way, the release of energy from ATP hydrolysis can be coordinated with movement of the helicase along DNA and DNA-unwinding activity.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–3
Figure 27–3

PcrA unwinds DNA by an inchworm mechanism. A series of crystal structures of the PcrA helicase bound to ATP and DNA substrates show an inchworm-like mechanism of DNA unwinding ( )(compare Fig. 27–4 ). The helicase moves in a 3’ →5’ direction along one DNA strand, separating it from the complementary strand. The 3’ tail of the DNA substrate binds in the cleft between RecA-like domains and presumably is drawn through the cleft during translocation. Interactions with the junction between single-stranded and double-stranded DNA (top of figure) are thought to destabilize base pairing and further promote DNA unwinding.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–4
Figure 27–4

Mechanisms of helicase-catalyzed DNA unwinding. Many mechanisms have been proposed for the DNA-unwinding activity of helicases, but most include elements of the active-rolling or inchworm mechanisms ( ). (A) The active-rolling model proposed as the mechanism of DNA unwinding by the dimeric Rep helicase ( ) involves the alternating binding of two Rep subunits to the single-stranded DNA/double-stranded DNA junction. Binding by the leading subunit promotes melting of DNA strands, and then a conformational change positions the other subunit in the leading position to advance the unwinding reaction. (B) The inchworm mechanism illustrated by crystal structures of the PcrA helicase ( ) (compare Fig. 27–3 ) involves conformational changes within a helicase monomer that slide the protein along the DNA in a processive manner. (C) The inchworm mechanism is analogous to the movement of two hands along a rod-shaped object. The hands alternate their grip on the rod as the hands slide apart and then back together, inching along the rod, as illustrated by the motion from 1A to 2A. These sliding motions involve conformational changes in the helicase that are coupled to the energy of ATP hydrolysis.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–5
Figure 27–5

DNA remodeling and double-stranded DNA translocation activities of ring-shaped helicases. A gel-based assay showed that the ring-shaped helicases DnaB and T7 gp4 can translocate on double-stranded DNA without strand separation occurring ( ). After the helicase loads on the 5’ single-stranded DNA tail, translocation on double-stranded DNA remodels a four-way DNA junction (Holliday junction), resulting in the products shown alongside the gel diagrammed here. (Individual strands identified as I to IV. Asterisks denote radiolabeled end.) DNA unwinding requires a substrate with an unpaired 3’ tail that is diverted to the outside of the helicase ring so that the strands are separated during movement of the helicase on the opposite strand in a 5’ → 3’ direction.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–6
Figure 27–6

Remodeling of a stalled replication fork by helicases such as RecG. (A) Structure of the RecG helicase on a DNA template with positioning of the leading and lagging strands and ADP as shown. (B) Helicases such as RecG catalyze the reversal of stalled replication forks, creating a four-way junction termed a “chicken foot” that is subject to excision repair or recombination ( ).

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–7
Figure 27–7

Technique used to evaluate SCE frequency. Cells are grown in the presence of BrdU for 24 h and, on average, have replicated their DNA once, resulting in one DNA strand on each chromatid having incorporated BrdU (unifiliarly). Each of these chromatids segregates to a new cell, and after another 24 h they have undergone another round of DNA replication. The chromosome then has one chromatid that has both strands of DNA labeled with BrdU (bifiliarly) and the other chromatid DNA strand unifiliarly labeled with BrdU. Individual DNA strands are shown for each chromosome or chromatid across the top of the figure. Chromosome spreads prepared from these cells are stained for detection of the unifiliarly labeled strand and can be visualized on a light microscope. After staining, double-stranded chromatids are shown as they would be visualized without individual DNA strands being identified. For every SCE, there is a change in the chromatids containing the stained DNA. This occurs occasionally in control cells and frequently in BS cells.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–8
Figure 27–8

Mitotic interallelic recombination. In mitotic cells, genetic recombination between homologs should be inconsequential since identical material is present on both. However, when the homologs contain different alleles, there can be consequences from interallelic recombination. While this was thought to be infrequent in mitotic cells, BS cells carrying two different mutations can reconstitute a wild-type allele both in vivo and in vitro following recombination. Depicted are the two different mutant alleles for the gene—one on each chromosome 15. The two different gene mutations are designated BLM-A and BLM-B, with the wild-type sequence at each of these sites represented by a + sign. For convenience, this patient is considered to be heterozygous for alleles at flanking polymorphic loci with the genotypes Aa, Bb, and Cc and alleles distributed on the two chromosomes as shown (top). A chromosome 15 bearing a wild-type locus and requisite flanking markers (designated a++BC) can be generated following interallelic recombination. This cell and all of its progeny will express normal BLM protein. Loss of heterozygosity for distal markers is illustrated for the cells in the dashed boxes at the bottom. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–9
Figure 27–9

Comparison of the RecQ helicases found in different organisms. The number of amino acid (aa) residues in each protein is indicated on the right. The conserved helicase (dark gold box) and nonconserved terminal domains (light grey box) are indicated. The region of homology C-terminal to the helicase domain is indicated as a light gold box. The exonuclease domains of WRN and FFA-1 are shown as dark grey boxes. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–10
Figure 27–10

Diagram of the distribution of wild-type BLM protein and mutant alleles using current nomenclature as defined at the Human Genome Variation Society website (http://www. HGVS.org). Stop codons are indicated by an X after the codon number. Domain organization and location are indicated under the diagram. N, N terminus; C, C terminus; NLS, nuclear localization signal. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–11
Figure 27–11

(A) Helicase substrates on which BLM and WRN can function. The lengths of the features of the substrate are indicated. All substrates are drawn with the 5’ end of the upper strand of the duplex on the left. (B) Graph of the comparative unwinding activity of BLM and WRN on the substrates. WRN is discussed later in this chapter. k is the pseudo-first-order rate constant of DNA unwinding. Gold bars indicate BLM protein unwinding, and grey bars indicate WRN protein unwinding. nt, nucleotide. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–12
Figure 27–12

Generation of a substrate containing a double Holliday junction. (A) Diagram representing the oligonucleotides and steps used in the construction of double Holliday junctions. (B) Diagram representing strand intertwinings that result in the formation of a topological link between oligonucleotides B1 and R1 present in double Holliday junctions. (C) Denaturing polyacrylamide gel electrophoresis (8% polyacrylamide) confirming the structure of the double Holliday junction in which oligonucleotide B1 is labeled (asterisk). Representations of the label in different molecules and their relative electrophoretic mobilities are shown. Lanes: 1, labeled B1 oligonucleotide; 2, double Holliday junction; 3 and 4, double Holliday junction digested with HhaI; 5 and 6, double Holliday junction digested with RsaI. The products in lanes 4 and 6 were treated with ExoI. (D) Denaturing polyacrylamide gel electrophoresis (8% polyacrylamide) confirming the structure of the double Holliday junction in which oligonucleotide R1 was labeled. Lane designations are as in panel C. The asterisks denote position of the radiolabel. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–13
Figure 27–13

BLM and TOP3A can convert double Holliday junctions into circular products. (A) A double Holliday junction was incubated alone (lane 3) or with increasing concentrations of BLM, as indicated. TOP3A was included in lanes 9 to 14. Labeled linear R1 and circular R1, as released by HhaI digestion of the double Holliday junction, were run as markers in lanes 1 and 2, respectively. The position of product P is indicated. (B) The reaction requires catalytically active TOP3A. The double Holliday junction was incubated alone (lane 2) or with increasing concentrations of either TOP3A (lanes 4 to 9) or TOP3A(Y337F) (lanes 10 to 15), as indicated. BLM was included in lanes 3 to 8 and 10 to 14, as indicated. Labeled linear R1 and circular R1 were run together in lane 1 as markers. Lanes labeled R1 or H denote RsaI or HhaI digestion, respectively, of the double Holliday junction complex with the labeled, single-stranded molecule running as shown. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–14
Figure 27–14

Relative number of apoptotic cells as a function of WRN genotype and camptothecin concentration. Cells were cultured in the presence or absence of camptothecin for 24 h. Solid lines represent WRN mutant cells, and dotted lines represent wild-type siblings from the same families. The degree of shading identifies sibling pairs. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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Image of Figure 27–15
Figure 27–15

Gene structure of and known mutations in RAPADILINO syndrome and RTS. The genomic structure of the helicase gene contains 21 exons and has a typical housekeeping promoter. The known RTS mutations are presented in the genomic sequence or in the cDNA sequence; stop codons are indicated by an X. In the figure, the helicase domain is indicated in dark gold. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Diseases Associated with Disordered DNA Helicase Function, p 947-978. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch27
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