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Chapter 12 : Mismatch Repair

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Abstract:

Both prokaryotic and eukaryotic cells have important systems for mutation avoidance that are capable of repairing mismatched base pairs in DNA. These mismatch repair (MMR) systems are highly conserved and play extremely important roles in the maintenance of genomic stability. Loss of MMR capability has a variety of significant biological consequences, including an increased susceptibility to cancer in mammals. This chapter reviews the critical discoveries that gave rise to our present understanding of MMR and its molecular mechanism. It also discusses the multitudinous biological roles of MMR besides avoiding mutations and preserving genomic stability. These include roles in cancer avoidance, regulation of homologous recombination, speciation, evolution and adaptive mutation, meiotic pairing and segregation, signaling of apoptosis in response to certain types of DNA damage, and hypermutation and class switch recombination in the immune response.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12

Key Concept Ranking

DNA Synthesis
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Genetic Recombination
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DNA Damage and Repair
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DNA Polymerase III
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Figures

Image of Figure 12–1
Figure 12–1

Use of heteroduplex molecules for measuring mismatch corrections. If the mismatch is corrected, all molecules generated by semiconservative DNA synthesis will be wild-type homoduplexes (right). However, in the absence of mismatch correction, 50% of the progeny molecules will be mutant homoduplexes (left).

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–2
Figure 12–2

Wagner-Meselson model for postreplicative mismatch correction of DNA. GATC sequences in DNA are normally methylated (Me) at the 6 position of adenine. During semiconservative DNA synthesis, a G-T mismatch arises in one of the sister DNA duplexes. The enzymatic mechanism for repairing this lesion depends on discrimination between the newly synthesized (gold) and parental (black) strands. This is achieved by recognition of the transient lack of methylation of the newly synthesized strand before postreplicative DNA methylation takes place. The nonmethylated daughter strand containing the incorrect base is enzymatically attacked by mismatch correction enzymes, and the misincorporated base is excised. Repair synthesis and daughter-strand methylation at GATC sequences restore the sister DNA duplexes to their native state. An alternative that Wagner and Meselson considered was that the strand discrimination was based on a special relationship between the MMR system and the replication fork ( ).

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–3
Figure 12–3

In vitro assay for mismatch correction. The substrate for MMR is a covalently closed heteroduplex of f1R229 containing a mismatch within the EcoRI site (positions 5616 to 5621). Methyl groups indicate the locations of the four d(GATC) sites within the DNA (positions 216, 1382, 1714, and 2221; the last of these is also a BamHI site). Cleavage of mismatch heteroduplexes with EcoRI and BamHI yields the full-length linear BamHI product, since the hybrid EcoRI site is resistant. Mismatch correction on the strand containing the mutant EcoRI sequence renders the site sensitive. Molecules repaired in this configuration thus yield two products on hydrolysis with the pair of endonucleases. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–4
Figure 12–4

Excision tracts generated in cell extracts by using circular substrates containing a mismatch and a single GATC site. The 6,440-bp covalently closed circular heteroduplex used in this work by Grilley et al. ( ) contained a G·T mismatch at position 5632 and a single d(GATC) sequence at position 216, which was modified on the viral or complementary DNA strand. Since hemimethylation imposes an asymmetry on the helix, heteroduplexes are designated according to the orientation of the unmodified strand. Molecules bearing complementary-strand methylation are referred to as 3’-heteroduplexes, since the unmodified d(GATC) sequence that directs repair is located 3’ to the mismatch along the shorter path (1,024 bp) separating the two sites in the circular molecule. The substrate with viral strand modification is designated a 5’-heteroduplex for a similar reason. During the reactions in cell extracts, DNA resynthesis was inhibited by dideoxynucleoside triphosphates. Electron microscopy visualization of DNA products produced under these conditions revealed the presence of single-strand gaps that spanned the shorter path between the mismatch and the d(GATC) site in the circular substrate. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–5
Figure 12–5

Circular and linear heteroduplex DNAs. Circular 6,440-bp and end-blocked linear 6,464-bp heteroduplexes were prepared. A hairpin oligonucleotide (10-bp stem, five thymidylate residues in the loop) present at each end renders the linear DNAs resistant to exonuclease attack in extracts. With the exception of topology and terminal sequences of linear molecules, the circular and linear substrates are identical, each containing a G·T mismatch and a single hemimethylated d(GATC) sequence. These two DNA sites are separated by 1,024 bp (a shorter distance in circular molecules). Since hemimethylation imposes an asymmetry on the helix, heteroduplexes are designated according to the d(GATC)-mismatch orientation on the unmodified strand, with circular molecules specified according to orientation along the shorter path. In 3’-heteroduplexes (modification on the complementary strand), the unmethylated d(GATC) sequence lies 3’ to the mismatch, while in 5’-heteroduplexes (methylation on the viral strand), this sequence is located 5’ to the mismatch. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–6
Figure 12–6

Mechanism of bidirectional methyl-directed MMR. Repair is initiated by activation of a latent MutH endonuclease in a reaction that is dependent on a mismatch, MutS, MutL, and ATP hydrolysis. The activated form of MutH cleaves the unmodified strand at a GATC site that can be located on either side of the mismatch. MutS and MutL help load helicase II (UvrD) in a biased fashion so that it unwinds toward the mismatch. Excision subsequently removes DNA spanning the two sites, with ensuing repair synthesis initiating near the GATC site or the mismatch, depending on the polarity of the unmodified strand. See the text for details. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–7
Figure 12–7

Illustration of how reduced proficiency of MMR of a heteroduplex generated by meiotic recombination can lead to a 3:5 or 5:3 segregation (postmeiotic segregation). If no MMR were to occur in the case illustrated, the result would be two postmeiotic segregations from the same meiosis (so-called aberrant 4:4 segregation). The 3:5 or 5:3 postmeiotic segregations can also arise from asymmetric strand exchange and no MMR ( ).

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–8
Figure 12–8

Neighbor-joining tree for Dayhoff PAM ( ) distances among MutS/MSH protein sequences. Gaps and regions of ambiguous alignment were excluded from the analysis. The horizontal scale bar indicates evolutionary distance. Numbers above each branch represent the number of times the branch was found in 100 bootstrap replicas. The and MutS protein sequences (gram-positive eubacteria) were used as an outgroup. The masked alignment used to generate this tree included the N-terminal, middle, and C-terminal regions. Differential shadings reflect the known functional role of each group: grey, eubacterial MMR and recombination; dark gold, mitochondrial MMR in eukaryotes; black, meiotic recombination in eukaryotes; light gold, nuclear MMR in eukaryotes. All eukaryotic homologs (MSH) are encoded by the nuclear genome, except for the mitochondrially encoded mtMutS from (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–9
Figure 12–9

Schematic view of excision products observed with 5 ‘ - and 3 ‘ -circular heteroduplexes in nuclear extracts of HeLa cells. Dashed lines indicate variability in observed excision tract end points. For the heteroduplex in which the incision is 3’ to the mismatch, products shown correspond to those derived from aphidicolin-inhibited reactions. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–10
Figure 12–10

Dependence of the 3’ excision reaction on MutS, MutL, EXOI, RPA, PCNA, and RFC. Reaction mixtures contained 24 fmol of incised 3’ A·T homoduplex (light gold) or 3’ G·T heteroduplex (dark gold; 141-bp nick and mispair separation distance). Concentrations of individual activities were varied as indicated, with amounts of the other five components fixed at the following concentrations: MutS, 390 fmol; MutL, 560 fmol; EXOI, 21 fmol; RPA, 900 fmol; and PCNA, 1,160 fmol. RPA titrations (upper right) were performed in the presence of variable amounts of RFC (dark gold; 220 fmol [standard amount]; black, 100 fmol; grey, 50 fmol). 3’-to-5’ excision was scored by cleavage with NheI and ClaI. Dotted vertical lines indicate the amount of each protein estimated by Western blot analysis to be present in 50 μg of HeLa nuclear extract. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–11
Figure 12–11

Recognition of a mismatch by an asymmetric MutS dimer. Crystal structures of ( ) and ( ) MutS proteins bound to a mismatched base pair or insertion-deletion loop, respectively, reveal a similar disk-shaped structure with the ATPase and DNA-binding domains located at opposite poles of the dimer. The DNA in complex with MutS is strongly kinked (ca. 60°), and it is held in this conformation by the mismatch-binding domain of one subunit and the clamp domain of the other subunit of the MutS dimer. The ATPase domains have a correspondingly asymmetric structure. Only the mismatch-binding subunit binds to ADP in the crystal structure, and the other ATPase domain is unoccupied. Thus, the two subunits of the dimer play unique roles in binding to ATP and DNA substrates, creating a structurally asymmetric dimer that signals the strand-specific cleavage of DNA at an unmethylated d(GATC) sequence to initiate MMR.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–12
Figure 12–12

Molecular basis for the detection of mispaired bases in DNA. The mismatch-binding domain of MutS directly contacts the unpaired bases of a G-T mispair ( ) or an insertion-deletion loop ( ) in crystal structures of MutS-DNA complexes. A conserved phenylalanine (F36 of MutS) inserts into the minor groove of the kinked DNA, and it stacks against the mispaired thymine base in both structures. The protein also forms hydrogen bonds with the unpaired bases, including the interaction of a conserved glutamic acid (E38 in MutS; not visible here) with the edge of the unpaired thymine. These interacting groups would not be exposed in normal Watson-Crick base pairs, and so these contacts are specific for mispaired bases in DNA.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–13
Figure 12–13

ATP binds to one subunit of the MutS dimer. Only the mismatch-binding subunit of MutS is configured to interact with an ATP cofactor. The phosphate-binding loop of the apposed ATPase domain from the other subunit is in an inactive conformation that partially blocks the nucleotide-binding site. The lack of symmetry within the ATPase domains of the MutS dimer is likely to stem from the nonequivalent interactions of each subunit with DNA, which direct the strand-specific cleavage of DNA during MMR.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–14
Figure 12–14

MutH resembles a type II restriction endonuclease. Conserved residues of the MutH active site lie at the junction of N-and C-terminal subdomains, which adopt slightly different conformations in different molecules of MutH that were crystallized ( ). The flexible structure of MutH might explain why association with MutL is required for DNA cleavage activity. Binding to MutL may stabilize the active conformation of MutH, limiting DNA cleavage activity to the proper context of the MutHLS complex.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–15
Figure 12–15

(A) Crystal structure of the MutL ATPase domain. The N-terminal domain of MutL was unexpectedly found to be an ATPase during the process of determining its structure by X-ray crystallography, and its activity was verified through biochemical studies ( ). It consists of two subdomains, an N-terminal ATP-binding module and a C-terminal mixed α,β-fold that contacts the ATPase module. The MutL ATPase is structurally homologous to the ATPase of DNA gyrase. The MutL ATPase dimerizes on binding to the nonhydrolyzable ATP analog AMPPNP or to ADP. The AMPPNP- and ADP-bound forms of MutL have different conformations—the presence of the “γ-phosphate brings the two subdomains close together for interactions with the bound nucleotide. ATP binding by MutL, and not hydrolysis, is required for activation of the MutH endonuclease. ATP turnover by MutL may constitute a conformational switch that regulates interactions with MutH and DNA cleavage activity during MMR ( ). (B) A docking model based on separate crystal structures of the MutL N-terminal ATPase domain and the MutL C-terminal dimerization domain suggests that the protein encircles DNA ( ). Residues within the C-terminal dimerization domain that are required for DNA-binding activity face the central cavity of MutL in the docking model. The ca. 20-bp DNA footprint of MutS is enlarged to almost 100 bp in the binary complex with MutL ( ), consistent with this proposal.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–16
Figure 12–16

Models to explain the logic of signal transduction necessary for correct MMR once the initial recognition of the mismatch has occurred. The grey sphere represents MutS/MutS. The figure does not attempt to represent the stoichiometry of any of the components. See the text for details.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–17
Figure 12–17

Evidence in support of various models for signal transduction in MMR once the mismatch has been recognized. (A) MutS-mediated DNA loop formation with heteroduplex DNA ( ). Samples were glutaraldehyde fixed and prepared for electron microscopy. HEPES-buffered reaction mixtures contained 15 μg of linear G·T heteroduplex per ml, 12.5 μg of MutS per ml, and 2 mM ATP. Incubation was carried out for 15 s. (B) ATP-induced release of MSH2-MSH6 from mismatched DNA requires a free DNA end ( ). MSH2-MSH6 binds a G·T mismatch or G·C homoduplex DNA oligonucleotide, which contains a 3’-biotin moiety on both the upper and lower DNA strand (b-G·T or b-G·C, respectively) after preincubation with streptavidin. D indicates unbound DNA substrate. DS indicates DNA complexed with one streptavidin molecule; DSS indicates DNA complexed with two streptavidin molecules. * indicates an hMSH2-hMSH6/DNA complex. hMSH2-hMSH6 binds a G·T mismatch or G·C homoduplex DNA oligonucleotide, which contains a 3’-biotin moiety oneitherthe top (3’-b) or bottom (5’-b). (C) Atomic force microscopy images of Mlh1-Pms1 binding to M13mp2 double-stranded DNA ( ). The gold arrow indicates a tractofcooperativelybound Mlh1-Pms1 associated with a single double-stranded DNAregion. The white arrow indicates a tract of cooperatively bound Mlh1-Pms1 associated with two double-stranded DNA regions of a single M13 molecule. (Adapted from references , and .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–18
Figure 12–18

Model for differential activation of EXOI-dependent 5’ or 3’ directed excision. Movement of the MutS-MutL complex away from the mismatch and along the helix has been postulated to signal excision system activation at the strand break that directs repair ( ). PCNA is loaded with a defined orientation at 3’ termini at a double-strand/single-strand junction ( ); i.e., the labeled PCNA face in the diagram is uniquely oriented relative to the 3’ end. Thus, a mobile MutS-MutL complex will encounter different orientations of the PCNA trimer depending on whether the strand break is located 5’ or 3’ to the mispair. In view of the ability of PCNA to interact with MutS-MutL and EXOI, this could result in orientation-dependent protein-protein interactions leading to differential activation of 5’ → 3’ or 3’ → 5’ hydrolytic activities of EXOI. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–19
Figure 12–19

A likely mechanism for duplication formation. Genetic exchanges between different sites on sister chromosomes can generate duplications and deletions. Many of the deletions are probably lethal, but large duplications cause no loss of gene function. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–20
Figure 12–20

Relative gene-targeting efficiencies of diverged substrates. The gene-targeting assay consists of three components: a chromosomally integrated nonfunctional gene (termed S2neo), which contains the 18-bp I-SceI endonuclease cleavage site, diverged repair substrates on circular plasmids (termed pneo), and an expression plasmid for the I-SceI endonuclease. With this design, a double-strand break introduced into the S2neo gene at the I-SceI site can be repaired from the homologous repair substrates to restore a gene. The frequency of colonies after double-strand break-induced recombination is plotted for cell lines transfected with each of the diverged pneo substrates [pneo-5mu (0.8% divergent), pneo-8mu (1.2% divergent), and pneo-10mu (1.5% divergent)] relative to frequencies of cell lines transfected with the wild-type (WT) pneo substrate. In each case, the transfection included the plasmid encoding SceI to induce a double-strand break at the S2neo gene. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–21
Figure 12–21

Relative number of transfer events occurring along the evolutionary trees of different genes. The relative number of transfers (t’) is expressed in terms of μ, the standard deviation from the mean calculated from the 10 housekeeping genes, and (light gold circles). The MMR genes and (dark gold circles) are more than three standard deviations from the mean. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–22
Figure 12–22

Double-strand break repair (DSBR) and synthesis-dependent strand annealing (SDSA) recombination models. A double-strand break is resected to expose 3’-end single-stranded tails, which invade the homolog and initiate DNA synthesis. A potential mismatch is indicated by a lollipop. In the DSBR model, on capture of the second end, DNA synthesis and ligation generate a double Holliday junction intermediate with heteroduplex DNA flanking the double-strand break site. Arrows indicate alternative patterns of resolution of junctions. Two of the four possible resolutions are shown; opposite-sense cutting generates crossovers, and same-sense cutting generates noncrossovers (see text). In the SDSA model, strand invasion occurs on only one side of the double-strand break. Repair is completed by synthesis and ligation. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–23
Figure 12–23

Model for the mechanics of human MSH4-MSH5 recognition of Holliday junctions. MSH4-MSH5 binding to a Holliday junction provokes ADP → ATP exchange and the formation of a hydrolysis-independent sliding clamp that links two homologous duplex DNA arms. Dissociation of one hMSH4-hMSH5 sliding clamp from the Holliday junction exposes the crossover to additional hMSH4-hMSH5 binding and clamp formation events. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–24
Figure 12–24

-MeG/MutS-dependent apoptosis in TK6 cells. TK6 (grey), TK6[MutS ] (dark gold), or TK6 + MGMT (light gold) cells were treated with 0.01, 0.02, 0.05, or 0.1 μg of MNNG per ml or left untreated. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–25
Figure 12–25

Impact of CdCl on mutation rates and viability in yeast. Frameshift mutation reporters with homonucleotide runs in the CG379 background included (A14 run that reverts by -1 frameshift), and (A7 run that reverts by +1 frameshift), and forward mutations, which arise by frameshifts, base substitutions, and gross rearrangements. Mutagenesis in wild-type (WT) and MMR-deficient strains is a function of CaCl concentration. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Figure 12–26

Production and repair of mismatches produced by the deamination of 5-meC in Boldface letters signify sites of these two events. (Adapted from reference .)

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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Image of Figure 12–27
Figure 12–27

Crystal structure of Vsr, an endonuclease specific for G·T mismatches. The Vsr endonuclease was crystallized in complex with DNA containing a G-T mispair ( ). Two Mg metal ions are bound in the active site of Vsr, and the DNA is cleaved 5’ to the mispaired T (left). The mismatched G·T forms a wobble base pair that stacks against a patch of conserved aromatic residues inserted into the double-stranded DNA helix (right panel; residues 1 to 26, which lie on top of the DNA in this view, are omitted for clarity). Recognition of the mismatch is accomplished without separation of DNA strands or base flipping. In vivo, MutS stimulates cleavage of DNA by Vsr at G·T mispairs.

Citation: Errol C, Graham C, Wolfram S, Richard D, Roger A, Tom E. 2006. Mismatch Repair, p 389-447. In DNA Repair and Mutagenesis, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816704.ch12
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References

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