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EcoSal Plus

Domain 4:

Synthesis and Processing of Macromolecules

DNA Methylation

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  • Authors: M. G. Marinus1, and A. Løbner-Olesen2
  • Editor: Sue Lovett3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester MA 01605; 2: Department of Biology, University of Copenhagen, DK-2200, Copenhagen N, Denmark; 3: Brandeis University, Waltham, MA
  • Received 11 March 2013 Accepted 08 November 2013 Published 06 June 2014
  • Address correspondence to M. G. Marinus, martin.marinus@umassmed.edu
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  • Abstract:

    The DNA of contains 19,120 6-methyladenines and 12,045 5-methylcytosines in addition to the four regular bases, and these are formed by the postreplicative action of three DNA methyltransferases. The majority of the methylated bases are formed by the Dam and Dcm methyltransferases encoded by the (DNA adenine methyltransferase) and (DNA cytosine methyltransferase) genes. Although not essential, Dam methylation is important for strand discrimination during the repair of replication errors, controlling the frequency of initiation of chromosome replication at , and the regulation of transcription initiation at promoters containing GATC sequences. In contrast, there is no known function for Dcm methylation, although Dcm recognition sites constitute sequence motifs for Very Short Patch repair of T/G base mismatches. In certain bacteria (e.g., , ) adenine methylation is essential, and, in , it is important for temporal gene expression, which, in turn, is required for coordinating chromosome initiation, replication, and division. In practical terms, Dam and Dcm methylation can inhibit restriction enzyme cleavage, decrease transformation frequency in certain bacteria, and decrease the stability of short direct repeats and are necessary for site-directed mutagenesis and to probe eukaryotic structure and function.

  • Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013

Key Concept Ranking

Gene Expression and Regulation
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DNA Synthesis
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Type III Secretion System
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Article Version

This article is an updated version of the following content:

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/content/journal/ecosalplus/10.1128/ecosalplus.ESP-0003-2013
2014-06-06
2017-11-21

Abstract:

The DNA of contains 19,120 6-methyladenines and 12,045 5-methylcytosines in addition to the four regular bases, and these are formed by the postreplicative action of three DNA methyltransferases. The majority of the methylated bases are formed by the Dam and Dcm methyltransferases encoded by the (DNA adenine methyltransferase) and (DNA cytosine methyltransferase) genes. Although not essential, Dam methylation is important for strand discrimination during the repair of replication errors, controlling the frequency of initiation of chromosome replication at , and the regulation of transcription initiation at promoters containing GATC sequences. In contrast, there is no known function for Dcm methylation, although Dcm recognition sites constitute sequence motifs for Very Short Patch repair of T/G base mismatches. In certain bacteria (e.g., , ) adenine methylation is essential, and, in , it is important for temporal gene expression, which, in turn, is required for coordinating chromosome initiation, replication, and division. In practical terms, Dam and Dcm methylation can inhibit restriction enzyme cleavage, decrease transformation frequency in certain bacteria, and decrease the stability of short direct repeats and are necessary for site-directed mutagenesis and to probe eukaryotic structure and function.

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Figures

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Figure 1

Structures of 5-methylcytosine and -methyladenine. doi:10.1128/ecosalplus.ESP-0003-2013.f1

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 2

The locations of promoters P1 through P5 are indicated, as is the transcription terminator (T) at the end of . The major and growth rate-regulated promoter P2 is located 3.2 kb upstream of the gene. doi:10.1128/ecosalplus.ESP-0003-2013.f2

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 3

TBLASTN searching was used with 4311 proteins against selected genomes with and without the gene. The genes encoding SeqA, MutH, HN-S, PriB, and 75 other proteins were found in all selected genomes with the gene and in none of the genomes lacking it. Reproduced from reference 2 with permission from Elsevier Ltd. doi:10.1128/ecosalplus.ESP-0003-2013.f3

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 4

Nucleophilic attack by cysteine-177 of Dcm at the C-6 position of cytosine leads to the formation of a covalent Dcm-DNA intermediate. This leads to activation of the C-5 position and transfer of the methyl group from SAM. The -adenosylhomocysteine (SAH) and the methylated cytosine are released from the covalent intermediate. doi:10.1128/ecosalplus.ESP-0003-2013.f4

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 5

Deamination of 5-meCyt in duplex DNA produces a T-G mismatch, which is a substrate for Vsr endonuclease. After removal of the T residue, DNA polymerase I and DNA ligase reactions restore the original sequence that is remethylated by Dcm. Failure to repair before DNA replication, or if the MutHLS mismatch system acts on the mismatch before Vsr, will produce a GC to AT mutation. doi:10.1128/ecosalplus.ESP-0003-2013.f5

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 6

The top of the figure shows DNA immediately behind the replication fork in which the “old” top strand is methylated and the “new” strand is not and also contains a base mismatch (carat) created as a replication error. The mismatch is recognized and bound by MutS followed by recruitment of MutL and MutH to form a ternary complex. The formation of this complex is thought to involve DNA looping to bring the mismatch and a GATC sequence in close proximity, but the details are unclear. In the ternary complex, the latent nuclease activity of MutH is activated and it cleaves the new unmethylated strand 5′ to the GATC sequence. The nick created by MutH serves as an entry site for the UvrD helicase which unwinds the DNA, exposing single-stranded DNA that is digested by one or more of the following exonucleases: RecJ, ExoVII, ExoX, or ExoI. The exonuclease(s) used depends on the relative orientation of the mismatch to the GATC sequence; in the figure, the direction of UvrD unwinding is 5′ to 3′, so either ExoVII or RecJ or both are needed. If the mismatch was to the “right” of the GATC sequence, UvrD would unwind in the 3′ to 5′ direction and ExoX and/or ExoI would digest the single-stranded DNA. The gap created by nuclease digestion removes the mismatched base and is filled in by DNA polymerase III. The resulting nick is closed by DNA ligase, and eventual Dam methylation precludes any further repair. doi:10.1128/ecosalplus.ESP-0003-2013.f6

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 7

(A) A replication fork encounters a mismatch repair (MMR) intermediate of a nick or gap on one strand leading to replication fork collapse. The MMR intermediate could arise from the processing of endogenous DNA damage or from repair of a replication error from the previous replication. Recombination between daughter chromosomal arms can restore the fork that can then be loaded with the DnaB helicase and DNA polymerase III holoenzyme. (B) MutH nicking on opposite sides of the same GATC in nonreplicating DNA produces a double-strand break that can be repaired by using a sister chromosome. (C) MMR processing of a replication error either by action at the same GATC as in panel B or by overlapping excision tracts from GATCs on opposite strands, producing a double-strand break that can be repaired using the daughter strands as template. (D) Mismatch repair-independent double-strand break formation. Asynchronous initiation of chromosome replication in a mutant could lead to two initiation events close together, resulting in two closely spaced forks on each chromosomal arm. If the second fork catches up to the first, replication fork collapse occurs. The exposed double-stranded end becomes a substrate for RecBCD exonuclease which, when encountering a Chi site, loads RecA on single-stranded DNA, thereby generating an SOS-inducing signal. doi:10.1128/ecosalplus.ESP-0003-2013.f7

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 8

Double-strand breaks (DSBs) in an mutant detected by single-cell microgel electrophoresis showing disrupted cells with 0, 1, or 2 double-strand breaks. Reproduced from reference 112 with permission from the American Society for Microbiology. doi:10.1128/ecosalplus.ESP-0003-2013.f8

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 9

Lrp binds cooperatively to either Lrp binding sites 1 to 3 (in the OFF-state, nonpiliated) or to the Lrp binding sites 4 to 6 (ON-state, piliated). Lrp binding site 3 overlaps the promoter and Lrp binding to site 3 inhibits transcription. Lrp binding sites 2 and 5 overlaps with GATC sites, and Lrp binding to either site prevents methylation of that site by DamMT. Lrp binding to sites 1-3 mutually excludes binding to sites 4-6. When in OFF-state, each DNA replication produces one hemimethylated GATC site (in Lrp site 5) and one unmethylated GATC site (in Lrp site 2) and dissociates Lrp from its binding sites. The OFF-state is preserved by rebinding of Lrp to the same binding sites around the unmethylated Lrp binding site. A shift from phase OFF to ON may occur if PapI mediates Lrp binding to the hemimethylated Lrp site 5, followed by Lrp binding to sites 4 and 6. The shift is further stabilized by full methylation of site 2 by DamMT and conversion of the hemimethylated site 5 to unmethylated by subsequent DNA replications. Adapted from reference 259 with permission from Cell Press (Elsevier). doi:10.1128/ecosalplus.ESP-0003-2013.f9

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 10

The promoter region of the gene contains three GATC sequences that must be methylated (Me) for the gene to be expressed. Replication of the gene will cause transient hemimethylation allowing one of three proteins to bind this DNA. Dam action will methylate the GATCs on the new strand, thereby preserving the expression of the gene. SeqA can also bind but is easily displaced by Dam, resulting in methylation and continued gene expression. OxyR binding prevents Dam action, and, after a second round of replication, the GATCs are unmethylated and transcription is prevented. doi:10.1128/ecosalplus.ESP-0003-2013.f10

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 11

In wild-type bacteria, both strands of IS are methylated (filled rectangles). Upon replication, two hemimethylated forms are produced, but only the form with the methylated coding strand actively transcribes the gene and moves to a new location, while the inactive IS remains. doi:10.1128/ecosalplus.ESP-0003-2013.f11

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 12

All genes for which a significant signal was obtained were plotted relative to wild type as a function of position along the chromosome. The chromosome is linearized at a position directly opposite . The replication origin has position 0 on the abscissa. (A) MG1655 . (B) MG1655_pTP166 (Dam overproducer). (C) MG1655 ::Tn. Trend lines for the gene expression data are presented in A and B. All points above the trend line in panel A; i.e., genes that were derepressed in the mutant are plotted as green dots, and all genes that were repressed in the mutant are plotted as red dots. Expression data from individual genes in panels B and C have the same color assignment as in panel A (red and green dots). Reproduced from reference 52 with permission from the National Academy of Sciences. doi:10.1128/ecosalplus.ESP-0003-2013.f12

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Figure 13

The genes for , , , and are shown together with their respective products. The genes are shown in the sequence they are replicated on the chromosome. Asterisks indicate CcrM recognition sites (GANTC). In addition to the genes shown in this figure, DnaA, GrcA, and CtrA control about 40, 50, and 95 other genes, respectively. Figure modified from reference 195 with permission of the National Academy of Sciences. Copyright 2007 National Academy of Sciences, USA. doi:10.1128/ecosalplus.ESP-0003-2013.f13

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Tables

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Table 1

DNA methyltransferases in K-12

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Table 2

K-12 alleles

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013
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Table 3

Altered physiological properties of a mutant ( 1 )

Citation: Marinus M, Løbner-Olesen A. 2014. DNA Methylation, EcoSal Plus 2014; doi:10.1128/ecosalplus.ESP-0003-2013

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