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Chapter 18 : Managing DNA Strand Breaks in Eukaryotic Cells

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Abstract:

This chapter presents a view of DNA double-strand break (DSB) repair that is focused primarily on the various pathways in eukaryotic cells, with only an occasional glimpse back at . As far as possible, unifying features that have been uncovered through studies of model organisms such as and multicellular lower eukaryotes are emphasized. The authors' initial view is focused on mechanistic descriptions of relevant strand break repair pathways, and this chapter starts with a general introduction followed by an in-depth discussion of homologous recombination and of alternative pathways that use homologous pairing to some extent, such as single-strand annealing (SSA) or break-induced replication (BIR). The complex topic of general recombination, especially with respect to meiotic recombination is briefly explained. Since homologous recombination is involved, the repair of is also summarized.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18

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Image of Figure 18–1
Figure 18–1

Overview of eukaryotic DSB repair pathways. A DNA DSB can be resealed by NHEJ without the participation of a homologous partner (see Chapter 19 for details). The alternative pathways are initiated by 5’ → 3’ single-strand resection. Strand invasion can result in the formation of a replication fork and an extended gene conversion tract (BIR). Following limited DNA synthesis, using another homologous chromosome or chromatid as a template, the invading strands may reanneal, and no crossover takes place (SDSA). However, in the classical HR scheme, Holliday junctions are resolved through symmetrical scissions following branch migration, resulting in gene conversion tracts in the vicinity of the DSB and possibly the crossover of flanking markers. Lastly, SSA refers to a process whereby single-strand degradation results in the exposure of homologous regions close to the DSB, usually on the same DNA molecule. The process results in annealing, single-strand clipping, and deletion of the intervening sequence. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–2
Figure 18–2

Detection of X-ray-induced DSB in chromosomal DNA by neutral sucrose gradient centrifugation. Sedimentation profiles of labeled yeast chromosomal DNA are shown before treatment (unirradiated control), immediately after X-ray treatment (300 Gy, 0 h), and following 3.5 h of postirradiation incubation (300 Gy, 3.5 h; gold lines). A shift to a lower average molecular weight is evident following X-ray treatment. The restoration of fast-sedimenting, high-molecular-weight DNA after incubation is observed in wild-type cells (RAD [left panel]). The latter is not detected in the mutant (right panel), which is defective in DSB repair and shows excessive degradation of nuclear DNA instead. The presence of a higher fraction of low-molecular-weight DNA than in the wild-type strain, even in unirradiated cells, can be attributed to the presence of degraded DNA in a subpopulation of nondividing cells found in mutant cultures. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–3
Figure 18–3

Detection of bleomycin- or γ-ray-induced DSB in chromosomes separated by orthogonal field alternation gel electrophoresis. (A and B) The original agarose gels. (C) Quantitative analysis of the band fluorescence in panel B. Note the decrease in signal intensities of individual bands in treated cells (bleomycin, 300 Gy) concomitant with an increase of DNA fluorescence interspersed between bands. The more slowly migrating, larger chromosomes are more susceptible to breakage. Restoration of the original profile after 24 h of incubation indicates repair of chromosomal DSB. Numbers at peaks (C) indicate chromosome assignment; certain chromosomes cannot be separated under these conditions. (Additionally, this diploid wild-type strain is heterozygous for the length of chromosome 3; note peaks 3a and 3b). (Panel A adapted from reference ; panels B and C courtesy of A. Friedl and F. Eckardt-Schupp.)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–4
Figure 18–4

Comet assay. (A) Various examples of the shapes of nuclei of mammalian cells subjected to ionizing radiation. (B) Parameters used to describe and possibly quantitate chromosomal damage. For example, the tail moment is defined as the product of tail length and fraction of total DNA in the tail. (Courtesy of G. Kyle, Perceptive Instruments Ltd.)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–5
Figure 18–5

Molecular detection of mating-type switching in following introduction of a targeted DSB by HO endonuclease. (A) The restriction maps indicate the alteration of the Y to Y region due to transfer of genetic information from the silent locus that is accompanied by the disappearance of the cut site and the acquisition of a novel StyI site. Corresponding fragments can be detected by Southern blotting of StyI-cut chromosomal DNA, using the probe indicated. (B) An experimental example is shown. Pulsed expression of HO endonuclease is accomplished by induction in galactose-containing medium followed by repression in glucose-containing medium. Over time, the 0.7-kb HO-cut fragment disappears at the expense of a 0.9-kb MATa fragment, indicating successful mating-type switching. In the deletion mutant, this process is only delayed (this mutant is discussed further in Chapter 19). In a mutant, this process is completely deficient. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–6
Figure 18–6

Detection of DSB-specific protein binding by using the chromatin immunoprecipitation assay. Following targeted DSB introduction, e.g., by using HO endonuclease expression (shown on the right), a suspected DSB-binding protein is immunoprecipitated using a specific antibody (Ab). DNA-protein cross-linking ensures the coimmunoprecipitation of the protein with bound chromosomal DNA from the vicinity of the HO site. Following cross-link reversal, a selected portion of this DNA can be amplified using PCR with appropriate primers. Gel electrophoresis may reveal a DNA product of the expected size. In the control without DSB, no specific DNA sequence is coimmunoprecipitated (left side), and the same PCR does not yield a significant amount of the DNA product. An experimental example is shown in Fig. 19–8 (see Chapter 19).

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–7
Figure 18–7

Detection of the repair of a targeted DSB in mammalian cells. (A) Recombination target and donor substrates are shown. Two defective gene versions have been integrated in a mammalian genome, rendering the cells neomycin sensitive. One carries an engineered site of the rare-cutting endonuclease I-SceI in a region where normally an NcoI site can be found the other is missing the 5’ region of the gene (3’ neo). Following I-SceI expression, the targeted DSB can be repaired by NHEJ, frequently resulting in alteration of the I-SceI site due to base deletions or additions Δ +) (to be discussed in Chapter 19). On the right, a gene conversion event involving HR results in the transfer of the NcoI site from the other gene copy (3’ neo) and in the emergence of a neomycin-resistant (neo) clone. (B) To discriminate between these events, chromosomal DNA is isolated at the times indicated after DSB introduction and used as a template for PCR with the primers shown above. The PCR products are digested with the restriction enzymes indicated. Over time, the acquisition of an NcoI site can be detected within the resulting 0.7-kb PCR product as an indication of gene conversion. Simultaneously, loss of the I-SceI site can be observed. (Adapted from references and .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–8
Figure 18–8

Sequence comparison of Rad51 protein and homologs isolated from fungal, plant, chicken, mouse, and human cells with RecA protein. The various proteins are aligned relative to a homologous core (domain II) containing motifs A and B of the ATP-binding consensus sequence of RecA (gold bars). The different black or grey areas indicate regions that are conserved only in a subfamily of these proteins. Open boxes indicate regions without apparent homol-ogy. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–9
Figure 18–9

Rad51 assembles into ring-shaped heptamers. (A) The crystal structure of full-length Rad51 ( ) reveals a C-terminal ATPase domain consisting of a Rossman nucleotide-binding fold, the elbow linker, and the N-terminal helix-hairpin-helix (HhH). The ATPase domain is structurally similar to the bacterial RecA protein and contains the signature Walker A and B motifs found in many nucleotide hydrolases. The elbow linker and HhH participate in subunit interactions. (B) In the absence of DNA, Rad51 can assemble into heptameric rings in which the N-terminal HhH domain packs against the ATPase active site of a neighboring subunit. This interaction may regulate ATP hydrolysis in response to assembly of the circular rings or extended filaments when bound to DNA.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–10
Figure 18–10

In vitro strand exchange assay. Circular ssDNA and linear dsDNA of identical sequence are incubated with various protein combinations. The substrates (SS, DS), the intermediate product indicating synapsis (JM), and the end product of strand exchange (OC) can all be separated by agarose gel electrophoresis as indicated. Rad51 alone is not able to catalyze a significant level of strand exchange. As shown by sequential addition, RPA can enhance this reaction but only if added after Rad51. The best yield is obtained by inclusion of both RPA and Rad52. Here, Rad52 can overcome the inhibitory effect of adding RPA before Rad51. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–11
Figure 18–11

Functional domains of Rad52. The location of domains mediating interaction with Rad52 itself, with Rad51, with the p34 subunit of RPA, and with DNA is depicted. The degree of homology (percent) between and human Rad52 is also indicated. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–12
Figure 18–12

Rad52 self-associates into a ring-shaped ssDNA-binding protein. (A) A three-dimensional reconstruction of electron micrographs of human RAD52 reveals a ring-shaped heptamer ( ). (B) In other studies, the crystal structure of an N-terminal fragment of human RAD52 (residues 1 to ) that has single-strand annealing activity shows assembly of an undecameric ring with a deep groove containing positively charged residues (grey). This groove is the proposed ssDNA-binding surface of RAD52. The other half of RAD52 (not present in the crystal structure) presumably mediates interactions with RAD51.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–13
Figure 18–13

Simplified scheme of the early steps of homologous recombination. Following single-strand degradation, RPA binding to ssDNA is required for the removal of secondary structure. The following replacement of RPA with Rad51 and the formation of a DNA-protein filament is mediated by Rad52. Following synapsis and strand exchange, the displaced single strand may again be coated by RPA. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–14
Figure 18–14

Phenotypes and activities conferred by Rad51 paralogs. In this scheme, the contacts made among the depicted proteins and the symbolized Rad51 helical filament reflect known protein interactions. The protein groups labeled A to D refer to protein complexes that have been isolated by various investigators.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–15
Figure 18–15

Rad54 changes DNA topology, and such change facilitates homologous strand pairing. (A) Relaxed-circular duplex DNA of phage ΦX is more susceptible to nicking by the single-strand-specific P1 nuclease in the presence of human RAD54, indicating partial strand separation. (B) Homologous pairing between a radioactively labeled, linear ssDNA fragment and a supercoiled circular duplex (sc), resulting in ATP-dependent D-loop formation, requires both RAD51 and RAD54. (Adapted from references [panel A] and [panel B].)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–16
Figure 18–16

Model for stimulation of Rad51-mediated homologous pairing by Rad54 movement. (A) The depicted interaction between Rad54 and the Rad51-coated single strand prevents rotation around DNA during tracking. (B) As a consequence, negative and positive supercoiling is introduced during Rad54 translocation. Negative supercoiling facilitates strand separation and joint-molecule formation of incoming ssDNA with homologous duplex DNA. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–17
Figure 18–17

Possible dual functions of Rad54 in enabling strand invasion and facilitating branch migration. The dissociation of otherwise inhibitory dsDNA-Rad51 complexes by Rad54 results in Rad51 turnover and assists in extending the heteroduplex region. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–18
Figure 18–18

Domain structure of BRCA1 and BRCA2. For BRCA1, the location of the RING finger domain, nuclear localization signal (NLS), and BRCT repeats are shown. The binding sites for BARD1 (BRCA1-associated ring finger domain), MRN complex, BRCA2, BACH1, C-terminal interacting protein (CtIP), and RNA Pol II (RNAP II) are also indicated. For BRCA2, BRC repeats and oligonucleotide-binding (OB) motifs are depicted. The latter are required for ssDNA binding. Six of the eight BRC repeats interact with RAD51. Other interacting proteins are the histone acetylase P/CAF, DSS1 (a protein deleted in the split-hand/split-foot syndrome), and BRAF35 (BRCA1 associated factor of 35 kDa). aa, amino acids. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–19
Figure 18–19

The BRC peptide motif caps the subunit interface of RAD51. The BRC repeat peptide (grey) from BRCA2 binds tightly to RAD51 (gold), blocking the subunit interface of RAD51 that mediates self-assembly into a filament. The crystal structure of the BRC-RAD51 complex reveals the details of the interaction ( ).

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–20
Figure 18–20

SSB domains of BRCA2. A crystal structure of a C-terminal region from the BRCA2 protein ( ) resulted in the discovery of OB-fold domains that are associated with ssDNA-binding functions (see chapter 8), suggesting a direct role of BRCA2 in recombination.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–21
Figure 18–21

(A) In vitro detection of Holliday junction resolution and branch migration. Branch migration can convert the synthetic α- shaped structure (top left) into a radioactively labeled (*) doublestranded linear fragment and an unlabeled nicked circle as indicated. Holliday junction resolution yields a labeled nicked circle and labeled linear fragment or a labeled linear dimer structure, depending on the orientation of cleavage (cut at 1/3 or 2/4). (B) The purified protein extract fraction SP-15 catalyzes branch migration and Holliday junction resolution. Depleting SP-15 of RAD51C and associated complexes using a polyclonal antibody eliminates the activity (SP-15 depl.). The activity is not restored by adding purified RAD51 but by adding one of several known RAD51C-containing complexes: RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2), RAD51B-RAD51C (BC), or RAD51C-XRCC3 (CX3). (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–22
Figure 18–22

SDSA and BIR as examples of DSB-induced, one-ended reactions. In both cases, the invading 3’ end is extended by DNA synthesis. For SDSA, DNA synthesis is limited and the extended strand is eventually displaced and anneals with the complementary single strand from the other DSB end. For BIR, a likely model involves the establishment of a replication fork and DNA synthesis using the displaced strand as a lagging-strand template, possibly to the end of the chromosome. In the end, one Holliday junction needs to be resolved. This is a likely mechanism to repair a broken telomere, resulting in a large region where heterozygosity is lost.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–23
Figure 18–23

DSB-initiated SSA. 5’ → 3’ degradation occurs bidirectionally at sites of breakage until homologous single-stranded regions are exposed. After annealing, nonhomologous 3’ overhanging sequences are excised. The Rad1-Rad10 endonuclease is required for this process. Remaining gaps are filled by repair synthesis and ligation. This mechanism leads to a deletion product with removal of the intervening DNA between the direct repeats. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–24
Figure 18–24

Plasmid system to monitor the repair of a targeted DSB by gene conversion or SSA. (A) The depicted centromeric plasmid contains two defective copies of as direct repeats def. One copy is inactivated by insertion of the recognition site for the HO endonuclease, and the other lacks a functional promoter. After induction of HO endonuclease expression, colonies can arise by transfer of information from the second copy, leading to a gene conversion event without crossover. Alternatively, the deletion of the intervening sequence by SSA results in a single expressed intact gene copy (see also Fig. 18–23 ). Probing DNA preparations digested with PstI (P), HindIII (H), and SmaI (S) with an internal fragment allows the detection of diagnostic fragments in Southern blots (compare panels A and B). Fragments of 1.8 and 2.6 kb indicate the presence of a DSB in the formerly 4.4-kb fragment containing the HO site. SSA results in the formation of a 5.8-kb PstI-SmaI fragment. The presence of a 4.3-kb HindIII-SmaI fragment indicates a gene conversion event. (B) The schematized gel shows the different kinetics for deletion formation and gene conversion; the 5.8-kb fragment is detectable at earlier times after HO endonuclease induction than is the 4.3-kb fragment. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–25
Figure 18–25

Pattern of incision by the UvrABC enzyme at psoralen monoadducts and interstrand cross-links. (A) Incision of monoadduct base damage by the UvrABC endonuclease occurs at the eighth phosphodiester bond 5’ and the fifth phosphodiester bond 3’ to the lesion, on the strand containing the base damage. (B) A psoralen cross-link is cut at the ninth phosphodiester bond 5’ and the third phosphodiester bond 3’ to the crosslink predominantly on the furan-adducted strand. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–26
Figure 18–26

Model for repair of DNA ICL in (A) Cross-linked DNA is shown. (B) The UvrABC endonuclease generates two incisions flanking the psoralen adduct on the furan-adducted DNA strand (incision ). (C) A gap is generated 3’ to the cross-link, for example by the 5’-3’ exonuclease of Pol I or by another UvrABC cleavage. (D) The gap is a substrate for RecA-mediated recombination utilizing an invading homologous DNA strand. (E) The other arm of the cross-link can then be incised by the UvrABC endonuclease (incision ), leading to the excision of a complex 11-or 12-mer oligonucleotide structure. (F) DNA repair is completed by repair synthesis and ligation.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–27
Figure 18–27

Representative models for ICL repair and tolerance in (A) Repair of an ICL by the formation of one DSB and homologous recombination resulting in break-induced replication. (A1) Incisions or a collision with a replication fork produce a DSB on the centromeric side of an ICL. (A2) The DSB end that does not contain the ICL is processed by a nuclease to yield a 3’ ssDNA tail. (A3) The ssDNA tail invades homologous dsDNA. The ICL-containing telomeric part of the chromosome is degraded. (A4) In a process of BIR, a replication fork is formed with both leading- and lagging-strand DNA synthesis to elongate both strands of the invading DSB end. DNA synthesis is continued up to the end of the chromosome. (A5) The Holliday junction formed by the DNA strand invasion is resolved. (B) Repair of an ICL by the formation of one DSB and homologous recombination resulting in single-strand annealing. (B1) A DSB is formed on one side of an ICL. (B2) The DSB end that does not contain the ICL is processed by a nuclease to yield a 3’ ssDNA tail. (B3) The ssDNA tail invades homologous dsDNA. DNA is synthesized starting from the invading strand. An incision is made in one DNA strand on the other side of the ICL. (B4) The newly synthesized DNA unwinds from the homologous DNA molecule. The nick on the other side of the ICL is processed into an ssDNA region by resection or unwinding of the DNA. This ssDNA region can anneal with the newly synthesized DNA strand. As a result, the ICL-containing DNA is displaced and forms a flap. Depending on the position of the ssDNA region and the length of the newly synthesized DNA strand, an ssDNA flap is produced on the other side of the annealing region as well. (B5) The flaps are removed by an endonucleolytic incision. The remaining gaps are filled in by DNA synthesis and ligation. (C) Bypass of an ICL at a stalled replication fork by recombination and translesion synthesis. (C1) An ICL causes arrest of a replication fork. Incisions in the lagging-strand template next to the ICL produce nicks on both sides of the ICL in the leading strand and a DSB on the DNA containing the lagging strand. (Similar events could occur when the first incisions are made in the leading-strand template.) (C2) The DSB is processed by a nuclease to form a 3’ ssDNA tail that invades the sister chromatid in front of the ICL. (C3) The cross-linked oligonucleotide is displaced, and DNA is synthesized from the invading end with a specialized DNA polymerase to bypass the ICL by translesion DNA synthesis. (C4) The newly synthesized DNA is ligated to a parental strand. Isomerization of this DNA structure could place the cross-linked oligonucleotide back into the helix. (C5) The cross-linked oligonucleotide is ligated to the rest of the leading strand, and replication fork progression is restored. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–28
Figure 18–28

Model for repair of an ICL, incorporating the unique incision properties of ERCC1-XPF. (A) A Y structure is created near a cross-link, for example by the progression of a DNA replication fork or by a DNA helicase. (B and C) ERCC1-XPF can cleave on the 3’ side of one arm of the cross-link (B) and then on the 5’ side (C). (D to F) After fork collapse, recombination and NER steps can then take place to complete repair. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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Image of Figure 18–29
Figure 18–29

One model for the mechanism of DNA ICL repair in mammalian cells. A DNA ICL is depicted as a gold line connecting the two strands. Newly replicated DNA is depicted by arrows (for clarity, no base-pairing is indicated between the template and the newly synthesized DNA strands). (A) Repair of an ICL is initiated during DNA replication. (B) The ICL prevents the unwinding of the two DNA strands, stalling the replication fork. (C) This leads to fork regression and the formation of a DSB. (D) The formation of a DSB creates a substrate for the ERCC1-XPF nuclease by revealing a 3’ end near the ICL. (E) ERCC1-XPF cuts the DNA on the other side of the break (see also Fig. 18–28 ). The incision releases the ICL from one of the two DNA strands. (F) The residual DNA damage may be bypassed by a DNA polymerase capable of translesion synthesis (indicated in gold). (G) Residual ICL damage may ultimately be excised from the second strand (potential cut sites are indicated by arrows). (H) The resulting gap could be filled by the replication machinery. (I) Repair of the DSB requires resection of the broken end to reveal a 3’ single-stranded overhang. (J) This 3’ end invades the template DNA to create a joint molecule. This is possible only when ERCC1-XPF has incised the blocking ICL. (K) Expansion of the heteroduplex could allow reestablishment of the replication fork. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Managing DNA Strand Breaks in Eukaryotic Cells, p 663-710. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch18
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