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EcoSal Plus

Domain 4:

Synthesis and Processing of Macromolecules

DNA Mismatch Repair

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  • Author: M. G. Marinus1
  • Editors: Susan T. Lovett2, Andrei Kuzminov3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St., Worcester MA 01605 USA; 2: Brandeis University, Waltham, MA; 3: The Schoold of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL
  • Received 08 September 2011 Accepted 12 December 2011 Published 24 August 2012
  • Address correspondence to M. G. Marinus martin.marinus@umassmed.edu
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  • Abstract:

    DNA mismatch repair (MMR) corrects replication errors in newly synthesized DNA. It also has an antirecombination action on heteroduplexes that contain similar but not identical sequences. This review focuses on the genetics and development of MMR and not on the latest biochemical mechanisms. The main focus is on MMR in , but examples from and have also been included. In most organisms, only MutS (detects mismatches) and MutL (an endonuclease) and a single exonucleaseare present. How this system discriminates between newlysynthesized and parental DNA strands is not clear. In and its relatives, however, Dam methylation is an integral part of MMR and is the basis for strand discrimination. A dedicated site-specific endonuclease, MutH, is present, andMutL has no endonuclease activity; four exonucleases can participate in MMR. Although it might seem that the accumulated wealth of genetic and biochemical data has given us a detailed picture of the mechanism of MMR in , the existence of three competing models to explain the initiation phase indicates the complexity of the system. The mechanism of the antirecombination action of MMR is largely unknown, but only MutS and MutL appear to be necessary. A primary site of action appears to be on RecA, although subsequent steps of the recombination process can also be inhibited. In this review, the genetics of Very Short Patch (VSP) repair of T/G mismatches arising from deamination of 5-methylcytosineresidues is also discussed.

  • Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5

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ecosalplus.7.2.5.citations
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/content/journal/ecosalplus/10.1128/ecosalplus.7.2.5
2012-08-24
2017-06-25

Abstract:

DNA mismatch repair (MMR) corrects replication errors in newly synthesized DNA. It also has an antirecombination action on heteroduplexes that contain similar but not identical sequences. This review focuses on the genetics and development of MMR and not on the latest biochemical mechanisms. The main focus is on MMR in , but examples from and have also been included. In most organisms, only MutS (detects mismatches) and MutL (an endonuclease) and a single exonucleaseare present. How this system discriminates between newlysynthesized and parental DNA strands is not clear. In and its relatives, however, Dam methylation is an integral part of MMR and is the basis for strand discrimination. A dedicated site-specific endonuclease, MutH, is present, andMutL has no endonuclease activity; four exonucleases can participate in MMR. Although it might seem that the accumulated wealth of genetic and biochemical data has given us a detailed picture of the mechanism of MMR in , the existence of three competing models to explain the initiation phase indicates the complexity of the system. The mechanism of the antirecombination action of MMR is largely unknown, but only MutS and MutL appear to be necessary. A primary site of action appears to be on RecA, although subsequent steps of the recombination process can also be inhibited. In this review, the genetics of Very Short Patch (VSP) repair of T/G mismatches arising from deamination of 5-methylcytosineresidues is also discussed.

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Figures

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Figure 1

Each chromatid is shown as two lines with each line representing one DNA strand at the pachytene stage of meiosis. The formation of heteroduplex DNA could occur with or without reciprocal exchange of flanking markers, as shown by the mixed black and red lines. Mismatch repair of the heterozygosity (a/+) in heteroduplex regions either toward the wild-type or mutant configurations would explain the aberrant segregation. That is, no recombination leads to normal segregation (A), but a reciprocal exchange and heteroduplex formation leads to aberrant 4:4 segregation (B). A reciprocal exchange followed by mismatch repair in favor of the wild type in one (C) or both (D) strands of the heteroduplex yields 5:3 and 6:2 segregation, while mismatch repair in favor of the mutant allele yields 3:5 and 2:6 segregation (E and F).

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Figure 2

Modified illustration from reference 7  used with the permission of Cambridge University Press.

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Figure 3

Transformation leads to the formation of heteroduplex DNA susceptible to mismatch repair (left), thereby reducing transformation frequency. Heteroduplexes not susceptible to mismatch repair yield high transformation frequencies.

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Figure 4

(A) Mutation frequency of induced mutant strains as a function of bromouracil concentration for the wild-type strain (open bars) and a mutant strain (filled bars). The wild-type strain shows no mutant induction at low (2% to 4%) bromouracil concentrations, consistent with a repair mechanism that becomes saturated at higher concentrations, yielding a concentration-dependent dose response. A mutant strain defective in repair () yields induced mutant cells at low (2% to 4%) bromouracil concentrations but also shows a mutator phenotype in the absence of mutagen. (B) Spontaneous Gal papillation on MacConkey agar of a strain (top) and the wild-type strain (bottom) (image supplied by the author).

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Figure 5

The substrate supercoiled molecule contains a single GATC sequence that can be methylated on either the viral (V) or complementary (C) strand (+/− or −/+) or both (+/+) or neither (−/−). A control molecule (0/0) contains a GATT sequence in place of GATC. The substrate also contains a T-G mismatch (carets) in the indicated sequence that is part of both a HindIII and an XhoI recognition site. Upon completion of the in vitro reaction in extracts or with purified components, the substrate DNA is digested with ClaI, HindIII, and XhoI. Correction of the mismatch will lead to resistance to one of the restriction enzymes. The substrate without the GATC (0/0) or a fully methylated GATC (+/+) shows no repair products, while the hemimethylated (+/− or −/+) or unmethylated substrates (−/−) show repair products derived preferentially from one strand. The figure has been modified from ( 55 ). Reprinted with permission from the American Association for the Advancement of Science.  

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Figure 6

The mismatch (carets) is bound by MutS (pierced circle) and MutL (red circles) leading to activation of the MutH endonuclease that can cleave either side of the mismatch. The mechanism leading to MutH endonuclease activation is not known. After cleavage, MutH is displaced by UvrD helicase, which unwinds the DNA toward the mismatch. Unwinding in the 5′ to 3′ direction results in digestion of the single-stranded end by ExoVII or RecJ. Unwinding in the opposite direction requires ExoI, ExoVII, or ExoX nucleases. The gap produced by excision is filled by DNA polymerase III holoenzyme. The resultant nick is sealed by DNA ligase, and Dam methylates the GATCs on the unmethylated strand, preventing further repair. The figure has been modified from reference 56 .

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Figure 7

(A) Single-stranded circular (SS) DNA anneals to its complement from double-stranded linear (DS) DNA to form a three-stranded intermediate (I) structure that forms a nicked circle (NC) and SS DNA as the products of the reaction. (B) The RecA strand transfer reaction using homologous M13-M13 DNA substrates (open triangles) is more rapid than the homeologous M13-fd reaction (open circles). Inclusion of MutS and/or MutL has no effect on the reaction with homologous DNA (data not shown). Inclusion of MutS in the reaction with homeologous DNA depresses the rate of the reaction (filled circles) and inclusion of both MutS and MutL (filled triangles) almost completely prevents formation of product. This figure is a modified version of one from the ( 133 ), used with permission. Copyright 1994 National Academy of Sciences, USA.

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Figure 8

Cells in the exponential phase of growth were exposed to cisplatin or MNNG at the indicated doses, and survival was determined by plating cells on nutrient agar plates.

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Image of Figure 9
Figure 9

(A) Replication of an OmeG base in the parental strand can result in the insertion of a T or G in the complementary strand. The mismatch repair system treats both types of base pairs as substrates, and a futile cycle of repair ensues. Repair can occur on either strand, and if it occurs on both strands simultaneously, a DSB may result because of overlapping repair tracts or by MutH (arrowheads) nicking at the same or closely spaced GATCs (black rectangles). (B) During futile cycling a second replication fork encounters the gap present during mismatch repair excision, which results in replication fork collapse.

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Figure 10

The RecA strand transfer reaction is as described in the legend to Fig. 7 . The rate of reaction with homologous DNA substrate with or without MutS and MutL addition is shown by the green circles. Modified substrate DNA with 5 to 10 OmeG residues per molecule reacted with homologous DNA is shown by the filled triangles. Modified substrate DNA with 5 to 10 OmeG residues per molecule reacted with homologous DNA and 25 μM MutS (open squares), 100 μM MutS (red squares), 25 μM MutS plus 50 μM MutL (multipliers), 100 μM MutS plus 100 μM MutL (open circles). This figure has been modified from one in ( 77 ), published by the Oxford University Press.

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Figure 11

(A) cultures of the indicated strains were irradiated with ultraviolet light, and samples removed at the indicated times to extract DNA. The DNA was then digested with T4 endonuclease V which nicks the DNA 5′ to the photoproducts. After electrophoresis in alkaline agarose the DNA was transferred to a membrane and hybridized with probes specific for the transcribed (T) or nontranscribed (NT) strands of the operon. The mutant strain is deficient in transcription-coupled NER. (B) Graphical representation of the results in panel A. Closed symbols represent the data for the transcribed strand, and open symbols represent the data for the nontranscribed strand. This figure is a modified version of one from the  ( 162 ), used with permission. Copyright 1996 National Academy of Sciences, USA.

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Image of Figure 12
Figure 12

The asterisk above the second cytosine in the top sequence denotes a 5-meCyt residue that can deaminate to form a T-G mismatch (center). In the reverse reaction, VSP repair restores the original sequence, and Dcm methylates the appropriate cytosine. The middle sequence can undergo two additional nonreversible reactions. If the mismatched DNA is replicated before repair, one of the daughter chromosomes will inherit a CG to TA mutation. Alternatively, the mismatched substrate is acted upon by mismatch repair converting the CG into a TA base pair.

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Image of Figure 13
Figure 13

The configurations of the two crosses between and are shown. In configuration I a single crossover will produce wild-type progeny, while three crossovers are needed in configuration II. The expected and observed recombination frequencies are shown beneath each configuration ( 186 ). In both cases, the observed recombination frequency is greater than the expected frequency due to VSP repair of the allele.

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Tables

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Table 1

Mismatch repair of heteroduplexes

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Table 2

proteins required for mismatch repair

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5
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Table 3

Conjugal crosses between and

Citation: Marinus M. 2012. DNA Mismatch Repair, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.5

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