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EcoSal Plus

Domain 4:

Synthesis and Processing of Macromolecules

Translesion DNA Synthesis

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  • Authors: Alexandra Vaisman1, John P. McDonald2, and Roger Woodgate3
  • Editors: Susan T. Lovett4, Andrei Kuzminov5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Laboratory of Genomic Integrity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892–3371; 2: Laboratory of Genomic Integrity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892–3371; 3: Laboratory of Genomic Integrity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892–3371; 4: Brandeis University, Waltham, MA; 5: The Schoold of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL
  • Received 28 July 2011 Accepted 10 November 2011 Published 19 March 2012
  • Address correspondence to Roger Woodgate woodgate@nih.gov
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  • Abstract:

    All living organisms are continually exposed to agents that damage their DNA, which threatens the integrity of their genome. As a consequence, cells are equipped with a plethora of DNA repair enzymes to remove the damaged DNA. Unfortunately, situations nevertheless arise where lesions persist, and these lesions block the progression of the cell's replicase. In these situations, cells are forced to choose between recombination-mediated "damage avoidance" pathways or a specialized DNA polymerase (pol) to traverse the blocking lesion. The latter process is referred to as Translesion DNA Synthesis (TLS). As inferred by its name, TLS not only results in bases being (mis)incorporated opposite DNA lesions but also bases being (mis)incorporated downstream of the replicase-blocking lesion, so as to ensure continued genome duplication and cell survival. and possess five DNA polymerases, and while all have been shown to facilitate TLS under certain experimental conditions, it is clear that the LexA-regulated and damage-inducible pols II, IV, and V perform the vast majority of TLS under physiological conditions. Pol V can traverse a wide range of DNA lesions and performs the bulk of mutagenic TLS, whereas pol II and pol IV appear to be more specialized TLS polymerases.

  • Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2

Key Concept Ranking

DNA Synthesis
0.8302151
DNA Damage and Repair
0.6067625
Nucleotide Excision Repair
0.44884458
DNA Repair Enzyme
0.41718304
Ribosome Binding Site
0.40934345
DNA Damage
0.4083828
Horizontal Gene Transfer
0.39866492
0.8302151

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ecosalplus.7.2.2.citations
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/content/journal/ecosalplus/10.1128/ecosalplus.7.2.2
2012-03-19
2017-04-26

Abstract:

All living organisms are continually exposed to agents that damage their DNA, which threatens the integrity of their genome. As a consequence, cells are equipped with a plethora of DNA repair enzymes to remove the damaged DNA. Unfortunately, situations nevertheless arise where lesions persist, and these lesions block the progression of the cell's replicase. In these situations, cells are forced to choose between recombination-mediated "damage avoidance" pathways or a specialized DNA polymerase (pol) to traverse the blocking lesion. The latter process is referred to as Translesion DNA Synthesis (TLS). As inferred by its name, TLS not only results in bases being (mis)incorporated opposite DNA lesions but also bases being (mis)incorporated downstream of the replicase-blocking lesion, so as to ensure continued genome duplication and cell survival. and possess five DNA polymerases, and while all have been shown to facilitate TLS under certain experimental conditions, it is clear that the LexA-regulated and damage-inducible pols II, IV, and V perform the vast majority of TLS under physiological conditions. Pol V can traverse a wide range of DNA lesions and performs the bulk of mutagenic TLS, whereas pol II and pol IV appear to be more specialized TLS polymerases.

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Figures

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Figure 1

(A) The original “two-step” model for UV-mutagenesis reported in 1984/1985 assumed that TLS in vivo is performed by the replicative pol III holoenzyme (consisting of catalytic core [α, θ, and ε], shown here and in  Figure 5 , Figure 6 , and Figure 7  as a yellow shape resembling a “right hand”; β-clamp, shown in Figure 1 , Figure 3 , Figure 5 , and Figure 9 as a yellow hexagonal shape; and γ-clamp loading complex, shown as a light orange five-subunit shape). The first step, nucleotide misincorporation opposite a 3′ Tof a cyclobutane pyrimidine dimer (CPD), was hypothesized to be mediated by the RecA protein (represented as a blue sphere in Figure 1 , Figure 2 , and Figure 9 ). The misincorporated base was subsequently fixed as a mutation in a second elongation/bypass step that depended upon the UmuC (shown in purple) and UmuD (orange shape) proteins ( 6 , 27 , 32 ). (B) Subsequent studies revealed that rather than being accessory factors of pol III, the products of genes encode a bona fide DNA polymerase, pol V (shown here and in Figure 3 , Figure 7 , Figure 8 , and Figure 9 as a purple UmuC and two orange UmuD subunits assembled in the shape of a “right hand”), which executes TLS in vivo ( 30 , 31 ). Thus, at a replication-blocking lesion, such as a cyclobutane pyrimidine dimer (CPD), pol III is replaced by pol VMut (UmuD'C-RecA-ATP complex) ( 33 ), which can carry out both the (mis)insertion and extension steps of TLS past the CPD. After traversing the damaged DNA, pol VMut is replaced by pol III holoenzyme, which resumes high-fidelity chromosomal duplication ( 34 ).

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Figure 2

The name and phylogenetic family relationship of each of 's five DNA polymerases and the number of amino acid residues in each polymerase are indicated on the right, while the name of the gene encoding the polymerase is noted on the left above the domain structure of each respective polymerase. The structural domains present in all polymerases are color coded as shown for pol I (palm, red; thumb, green; finger, blue). The palm domain consists of two segments separated by the insertion of the finger domain for all polymerases except pol III (α-catalytic subunit), in which the thumb domain separates these two segments. The five DNA polymerases have been aligned to the smaller segment of the palm domain. Other domains are as follows: 5′-3′ exonuclease of pol I, shown in orange; 3′-5′ exonuclease of pol I and pol II, shown in violet; N-terminal domain of pol II, in yellow; little finger of pol IV and pol V, in purple; PhP (polymerases and histidinol phosphatase) domain, in light blue. The region of the DnaE that binds to the ε-(3′-5′ proofreading) subunit of pol III is indicated by a semitransparent grey box labeled “ε.” Other regions of DnaE that mediate protein-protein and protein-DNA interactions are the “helix-hairpin-helix” (HhH, shown as a dark blue hexagon) and oligonucleotide/oligosaccharide binding (OB, shown as a grey box) domains. The HhH domain provides binding to double-stranded DNA (dsDNA), while the OB domain is involved in preferential interaction with single-stranded DNA (ssDNA). The finger domain of DnaE has four subdomains (marked by dark blue vertical bars). The acidic catalytic residues of each DNA polymerase are indicated in the diagram as dark red vertical sticks. The narrow yellow ovals mark the region of each polymerase that mediates their respective binding to the β-clamp.

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Figure 3

In uninduced cells, LexA (shown as a yellow homodimer in which each monomer consists of an N-terminal DNA-binding domain and a C-terminal dimerization domain) represses expression of TLS polymerases (pol II is represented here and in Figure 3 , Figure 7 , and Figure 8 as a dark blue “right hand” shape, and pol IV is shown here and in Figure 5 , Figure 6 , and Figure 7 as a green “right hand” shape with a blue “little finger” domain, as well as both UmuC and UmuD subunits of pol V) to a different extent depending on the H.I. of the LexA-binding site in the respective operator/promoter region of each polymerase. The H.I. also determines how soon after LexA cleavage expression of each gene is derepressed. DNA damage-induced formation of a RecA nucleoprotein filament on ssDNA mediates autocleavage of LexA and the derepression of genes in the LexA-regulon. It also mediates autocleavage of UmuD to UmuD'. Uncleaved and cleaved UmuD and UmuC form different complexes, of which UmuD'C is the most stable. UmuD' is targeted for degradation by ClpXP through preferential formation of UmuD/UmuD' heterodimers. Both UmuC and UmuD are unstable and rapidly degraded by the Lon serine protease. However, UmuC is stabilized by the GroEL and GroES molecular chaperones. The gene products also stabilize pol IV. In addition to SOS induction, pol IV expression is also stimulated by RpoS (represented by a pink arched shape) in stressed cells. Upon repair of DNA damage, the disappearance of the RecA filament allows the newly synthesized LexA molecules to block transcription of all LexA-regulated genes, and as a consequence, the intracellular concentrations of TLS polymerases return to their basal uninduced levels.

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Figure 4

Surface representation of a UmuD' dimer (Protein Data Bank [PDB] access code, 1UMU). One protomer is colored pale gray, and another one is colored pale orange. In this orientation, the active site (Ser60 is shown in red and Lys97 is in blue) of the gray protomer is clearly visible at the end of a cleft in the UmuD' protein. By forming such a dimer, the N-terminal tail of the pale orange UmuD' protomer is brought into relatively close proximity with the active site of its gray dimer mate ( 82 , 83 ). It is thought that a similar configuration is assumed during RecA-mediated cleavage of UmuD and that such protein-protein interactions promote intermolecular UmuD cleavage ( 84 , 85 ). The figure was generated with the program GRASP ( 86 ) and is reproduced with permission from McDonald et al. ( 85 ).  

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Figure 5

The cartoon depicts pol III (yellow) and pol IV (green with a blue little finger) simultaneously bound to the dimeric β-clamp. (A) The main replicase, pol III, is engaged at the primer terminus. (B) At a DNA lesion, pol III disengages from the primer terminus and pol IV rotates into position so as to promote TLS. (C) After TLS has occurred, pol IV is replaced by pol III, which resumes genome duplication. This cartoon is based on the “tool belt” model originally proposed by Pagès and Fuchs ( 115 ).

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Figure 6

Recent data suggest that pol IV can efficiently and accurately insert nucleotides opposite -dG adducts, such as those generated by exposure to nitrofurazone, as well as to extend from the resulting primer termini. As a consequence, cells devoid of are much more sensitive to the killing effects of nitrofurazone-induced adducts ( 189 ).

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Image of Figure 7
Figure 7

Different DNA polymerases may be involved in TLS of benzo[]pyrene (BaP) adducts depending on the sequence context surrounding the damaged site, conformation of the adduct, and identity of the damaged template base (A versus G) ( 40 , 105 , 180 , 184 , 194 , 195 ). For example, in SOS-induced cells both error-free TLS and −1 frameshift TLS of BaP located within a short run of Gs have been shown to depend largely on pol V and pol IV ( 60 , 196 ). In this case, bypass is initiated from the correct incorporation of C opposite the dG-BaP. This intermediate product could either be elongated in an error-free manner or adopt a slipped conformation, the elongation of which would result in −1 frameshift mutation. The SOS-independent G-to-T base substitution pathway consists of misincorporation of a dA opposite the dG-BaP and elongation of an A-lesion terminus, with both steps likely to be carried out by pol III and/or pol II ( 180 , 184 ).   

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Figure 8

Either pol V or pol III can insert a base opposite an AAF-dG lesion, and both do so in a relatively error-free manner (shown on the left). Pol V can extend the primer terminus leading to error-free TLS of the AAF-dG adduct. Alternatively, when the AAF-dG lesion is positioned in the 3′-CG sequence context and pol II performs the extension step (righthand side), −2-bp frameshifts occur ( 46 , 180 ).  

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Image of Figure 9
Figure 9

(A) In 1999, TLS was reconstituted in vitro in the presence of UmuD'C (pol V), β-sliding clamp, and RecA protein ( 30 , 31 ). Based upon genetic experiments in vivo ( 63 ), it was tacitly assumed that RecA stimulated pol V by forming a nucleoprotein filament on the ssDNA immediately 3′ of the stalled replication complex. (B) However, in 2006 it was demonstrated that pol V can also be activated in by interacting with the 3′ tip of RecA filament formed on a separate ssDNA molecule ( 206 ). (C) In 2009, it was subsequently determined that the highly active complex responsible for in vivo TLS is pol V Mut, which consists of UmuD'C•RecA•ATP and is formed by the transfer of a single RecA protomer along with ATP from the 3′ tip of a RecA nucleoprotein filament to pol V ( 33 ).  

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Image of Figure 10
Figure 10

(A) Structure of pol II with DNA containing abasic site and dATP (PDB accession code, 3K5L) ( 209 ). (B) Crystal structure of the Dpo4 ternary complex (PDB accession code, 1JX4) ( 213 ). The domains of both polymerases are color coded as follows: palm,  red; thumb,  green; finger, blue; exonuclease of pol II, violet; N-terminal domain of pol II, yellow; little finger of Dpo4, purple. The template strand is shown in a rust color, while the primer is olive green. The incoming dATP is shown in yellow. The small blue spheres represent the two metal ions. The protein backbone is represented by ribbon surrounded by semitransparent solvent-accessible surface. The structures were created by using Discovery Studio Visualizer. Comparison of these structures reveals that the active site of Dpo4 is significantly more spacious than that of pol II, allowing for the accommodation of bulky DNA lesions. The active site of pol II is very similar to that of high-fidelity replicative polymerases, but relaxed interactions with the upstream DNA template and an altered partitioning between the polymerase and exonuclease active sites ensure the participation of pol II in TLS.  

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Figure 11

(A) Model of a pol IV (shown in red) bound to the β-clamp (gold) in an inactive position. The position of the polymerase was modeled by superimposing the LF domain from the ternary complex of Dpo4 with DNA and an incoming nucleotide (PDB code, 1JXL) ( 213 ) onto the LF of pol IV (blue) in a complex with the β-clamp (PDB code, 1UNN) ( 103 ). In this position, pol IV is unable to access the primer/template terminus. (B) Model of pol IV bound to the β-clamp and DNA at the primer/template junction following a polymerase switch. The position of the polymerase was modeled by superimposing the DNA from the ternary complex of Dpo4 onto the end of a DNA molecule running perpendicularly through the β-clamp. Contact with the clamp is maintained by the C-terminal clamp-binding peptide (pink), which tethers the polymerase to the replication complex. (C) Dpo4 in an inactive extended form bound to PCNA (PDB code, 2NTI) ( 234 ) with dsDNA passing through its central aperture. In this conformation, the core (red) and LF (blue) of Dpo4 contact PCNA (the trimer is shown in yellow, orange, and brown) to facilitate the PIP (pink)-PCNA1 (yellow) binding. (D) Model of Dpo4 in an active form bound to a DNA template and a PCNA ring. Similar to the structure shown in the panel C, in this conformation the PIP-box anchors Dpo4 to PCNA1. The DNA-bound Dpo4 is modeled onto PCNA from the type I structure (PDB code, 1JX4). Panels A and B are reproduced with permission from Bunting et al. ( 103 ). Panels C and D were provided through the courtesy of Hong Ling, University of Western Ontario, London, Ontario, Canada. All four structures provide structural support for the proposed tool belt model for polymerase switching ( 115 ). 

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Figure 12

(A) Crystal structure of a UmuD' “Molecular” dimer (PDB code, 1AY9) in which the N termini of each protomer are extended in diametrically opposite directions ( 235 ). (B) Crystal structure of UmuD' “Filament” dimer (PDB code, 1UMU) in which the N-terminal tail of each protomer crosses over the globular body of its partner in a configuration that is likely to mimic the one in which the RecA-mediated cleavage of UmuD to UmuD' occurs ( 83 ). (C) NMR solution structure of UmuD' (PDB code, 1I4V) revealing a structural fold similar to the crystallographic “Filament” dimer, but in which the globular domain is somewhat “flattened” and the N-terminal tails are free in solution ( 82 ). The protein backbone is depicted as a tube that is surrounded by the semitransparent solvent-accessible surface of the dimer. One UmuD' protomer is colored yellow, while the other one is in orange. The structures were created with Discovery Studio Visualizer.  

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Image of Figure 13
Figure 13

(A) The genetic map locations and genomic architecture of the , , and genes are depicted. (B) The genetic map locations and genomic architecture of the serovar Typhimurium , , and genes are depicted. The location and context of the and serovar Typhimurium and genes are quite conserved. In contrast, the and serovar Typhimurium operons are located in different positions on the genetic maps, bordered by different genes, and in opposite orientations.

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Figure 14

The alignment of various HumD-like proteins was performed using MacVector 11.0.4. The HumD-like proteins include STM2230.1c (serovar Typhimurium; NP_461173), SPAB_00769 (serovar Paratyphi; YP_001587027), P1 HumD (YP_006569), P7 HumD (ZP_07505015), pO111_2 HumD (YP_003238012), fKO2 HumD (YP_006603), N15 HumD (NP_046921), and Ent638_1055 ( sp. strain 638; YP_001175788). Coloration indicates the degree of similarity to the consensus sequence. Blue indicates identity to the consensus, while green indicates an amino acid residue that is highly similar to the consensus. The degree of similarity to the consensus further decreases in the following order of coloration: yellow, orange, pink, and white.

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Tables

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Table 1

Intracellular concentration of DNA polymerases in

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Table 2

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2
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Table 3

Citation: Vaisman A, McDonald J, Woodgate R. 2012. Translesion DNA Synthesis, EcoSal Plus 2012; doi:10.1128/ecosalplus.7.2.2

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