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Mutational analysis of the 3[prime]->5[prime] proofreading exonuclease of Escherichia coli DNA polymerase III
Introduction
Materials And Methods
Strains and media
Mutant frequency determinations
Complementation assays
Sequencing of dnaQ genes
Results
Discussion
Acknowledgements
References
Mutational analysis of the 3[prime]->5[prime] proofreading exonuclease of Escherichia coli DNA polymerase III
ABSTRACT
INTRODUCTION
The structural and functional organization of DNA polymerase III holoenzyme, the chromosomal replication enzyme in Escherichia coli (1,2), is of significant current interest. The holoenzyme is composed of a total of 18 subunits, of which 10 are distinct (for a review, see 3). The enzyme is dimeric, containing two pol III core subassemblies, each containing three tightly-bound subunits in a linear arrangement, [alpha]-[epsis]-[thetas]. The dimeric structure of the pol III holoenzyme allows simultaneous replication, by a single pol III holoenzyme molecule, of both the leading and the lagging strand at the replication fork. The [alpha] subunit, the product of the dnaE gene, contains the polymerase. The [epsis] subunit, the product of the dnaQ (or mutD) gene, contains the 3[prime]->5[prime] exonuclease that functions as a proofreader for replication errors. The role of [thetas], the product of the holE gene, is as yet unknown. Additional subunits within the pol III holoenzyme include the [tau] subunit, which functions in dimerizing the two cores; the [beta] subunit, which forms sliding clamps that tether the core polymerases to the DNA, thereby conferring high processivity; and the [gamma] complex ([gamma],[delta],[delta][prime],[chi],[psi]), which functions in loading the [beta]-clamps onto the DNA. The precise functioning of the various subunits in the complex as well as their interactions are being actively studied (e.g. 4-8).
The present study focuses on the structural and functional properties of the [epsis] subunit within the pol III core. The 3[prime]->5[prime] exonuclease of the [epsis] subunit serves as the proofreader for DNA replication errors and thereby contributes to the high fidelity of DNA replication. This fidelity is generally considered the product of three serial steps: base selection, proofreading and post-replicative mismatch repair, resulting in an observed error rate of ~10-10 per base pair replicated (9,10). To this, proofreading may contribute a factor of ~10-2-10-3 (9,11). In addition to its proofreading activity, [epsis] likely plays an important structural role within the pol III core or holoenzyme, as predicted from its tight interactions with the [alpha] and [thetas] subunits. This prediction is supported by observations that the [epsis] subunit stimulates both the polymerase activity and processivity of the [alpha] subunit (12,13) and that conversely, [alpha] greatly stimulates the 3[prime] exonuclease activity of [epsis] (12). Recessive dnaQ(Ts) mutants exist that are inviable at high temperatures in salt-free media. This has been ascribed to the intrinsic instability of the holoenzyme or [alpha] subunit in the absence of [epsis] (14). Finally, strains containing deletion of dnaQ are essentially inviable, requiring the presence of stabilizing suppressor mutations in the [alpha] subunit (15). These combined data suggest that [epsis] plays an important structural role in pol III holoenzyme, likely in stabilizing [alpha] and, possibly, serving as a bridge to the [thetas] subunit, although the function of the latter subunit is still unclear (16).
Both structurally and functionally, little is known about [epsis] or its interactions with other subunits. In contrast to most DNA polymerase-associated 3[prime]->5[prime] exonucleases, which are part of the same polypeptide as the polymerase, [epsis] is a separate subunit. Amino acid alignments among polymerase-associated exonucleases have revealed several homologous regions containing conserved amino acid residues (Exo motifs). Blanco et al. (17) defined three such conserved Exo motifs: Exo I, Exo II and Exo III, each containing several highly conserved residues. The importance of these residues within the motifs has been supported by site-specific mutagenesis experiments on a variety of polymerases from different organisms (18-26). However, studies on the 3[prime]-exonuclease of Bacillus subtilis DNA polymerase III suggested that the Exo III motif, as defined by Blanco et al. (17), is absent in this enzyme (27). Instead, the authors identified an alternative motif, which they termed Exo III [epsis]. This name was chosen as alignments identified a similar motif in the E.coli pol III [epsis] subunit (27). While the importance of the conserved residues in B.subtilis Exo III[epsis] was supported by site-specific mutagenesis experiments on this enzyme, no corresponding studies have yet been performed on the [epsis] subunit. To date, only limited information exists with regard to the important residues in E.coli [epsis] and their functions (28,29). More recent, extensive alignments (30) encompassing a total of 148 3[prime] exonucleases, including both DNases and RNases, have placed [epsis], along with the proofreading exonucleases of the gram-positive pol IIIs and, interestingly, a series of RNases T, in a distinct subgroup of exonucleases characterized by the Exo III[epsis] motif.
To gain further insight into functionally and/or structurally important residues of the [epsis] subunit, we have investigated a series of E.coli dnaQ mutants. These mutants were detected based on their high spontaneous mutability (mutator phenotype), presumably resulting from defective or impaired proofreading. In this study, we correlate the amino acid sequence changes in the mutants with the strength of the mutator phenotype and with the dominant or recessive nature of the mutations. Together, these data provide independent evidence for the biological significance of the conserved residues, including those in the Exo III[epsis] motif. In addition, the data allow us to discuss the possible catalytic or structural roles of the affected residues.
MATERIALS AND METHODS
Strains and media
The dnaQ mutator alleles were isolated in three different experiments, each based on localized mutagenesis of the dnaE-dnaQ region of the chromosome using hydroxylamine-treated P1 phage as described (31) and papillation assays to detect mutators. The papillation assays were based on reversion of the galK2 allele (32), yielding dnaQ918 through dnaQ924, reversion of the lacZ75 frameshift allele (J.-Y.Mo and R.M.Schaaper, unpublished data) yielding dnaQ927 through dnaQ933, or reversion of the lacZ allele from strain CC105 (33) yielding dnaQ942 through dnaQ950 (unpublished data). For the mutagenesis experiments of Figure
Mutant frequency determinations
To determine the mutant frequencies of Figure
Complementation assays
The dnaQ alleles were transduced into mutL strains NR9501 or NR9606 as described above. The dnaQmutL double mutators were electroporated with pSTB101 (dnaQ+) and plated on LB containing spectinomycin. Mutant frequencies were determined by growing dnaQmutL, with or without pSTB101, in LB overnight at 37°C, and Rifr mutant frequencies were determined as described above. Comparison of mutant frequencies in the presence or absence of the plasmid resulted in classification of the dnaQ alleles as dominant, partially dominant or recessive (Fig.
Sequencing of dnaQ genes
For dnaQ918 through dnaQ933, the mutant genes were first cloned into pBluescript (KS+) as a 1.6 kb EcoRI fragment. Chromosomal DNA from each of the dnaQ mutator strains was isolated using the Easy DNA Kit (InVitrogen), restricted with EcoRI, size-purified on a 1% agarose gel and ligated into EcoRI-linearized pBluescript (KS+). The ligated DNA was transformed into strain NR10187 followed by plating on LB-Amp plates at 37°C. NR10187 is temperature sensitive due to the simultaneous presence of the dnaQ49 and dnaE915 (31) alleles; however, growth at 37°C is restored by temperature-resistant dnaQ alleles. Single-stranded DNA for DNA sequencing was generated by infecting selected transformants with helper phage VCM13 (Stratagene) as per Stratagene single-stranded rescue protocol. DNA sequencing was by the single-stranded protocol provided with 35Sequetide (Dupont NEN). Seven different primers covering the gene were used and each dnaQ allele was sequenced in its entirety. Alleles dnaQ942 through dnaQ950 proved difficult to clone by the above procedure, presumably due to the very high mutation rates associated with their proofreading deficiencies. For these alleles, two dnaQ specific primers, 5[prime]-TTCTCGCGTCCGCGATAGCG-3[prime] (forward primer) located at positions 1173-1154 and 5[prime]-TGCCTCGACCTCGTCAACGG-3[prime] (reverse primer) located at positions 189-208 (numbering system as in 14) were used to PCR amplify the chromosomal DNA containing the dnaQ gene. Single-stranded DNA for DNA sequencing was generated in an asymmetric PCR reaction using the double-stranded PCR product as template. DNA sequencing on the single-stranded DNA was performed as described above for dnaQ918 through dnaQ933.
Table 1.
| Allele | Base changea | Amino acid change | Complementation phenotypeb | |
| mutD5 | C967->Tc | Thr 15 Ile | D | (4, 150) |
| dnaQ49 | A725->Cd | Val 96 Gly | R | (55, 1) |
| dnaQ918 | G965->A | Thr 16 Ile | PD | (19, 5) |
| dnaQ920 | G846->A | Arg 56 Trp | D | (5, 7) |
| dnaQ921 | C473->T | Gly 180 Asp | PD | (25, 2) |
| dnaQ922 | C473->T | Gly 180 Asp | PD | (15, 2) |
| dnaQ923 | G816->A | His 66 Tyr | PD | (7, 4) |
| dnaQ924 | G501->A | Leu 171 Phe | PD | (5, 3) |
| dnaQ927 | C473->T | Gly 180 Asp | PD | (19, 2) |
| dnaQ928 | C963->T | Gly 17 Ser | D | (5, 9) |
| dnaQ930 | GG720,721->AA | His 98 Tyr | D | (6, 6) |
| dnaQ932 | CC290,291->TT | Trp 241 STOP | R | (31, 1) |
| dnaQ933 | CC473,474->TT | Gly 180 Asn | D | (5, 5) |
| dnaQ942 | C513->T | Asp 167 Asn | PDe | |
| dnaQ943 | C523->T | Ala 164 Thr | PD | (15, 22) |
| dnaQ944 | C518->T | Asp 167 Asn | PD | (10, 88) |
| dnaQ945 | G522->A | Ala 164 Val | PD | (17, 18) |
| dnaQ946 | G522->Af | Ala 164 Val | PD | (8, 30) |
| dnaQ947 | C972->T | Glu 14 Lys | PD | (23, 31) |
| dnaQ948 | C978->T | Asp 12 Asn | D | (4, 53) |
| dnaQ949 | C705->T | Asp 103 Asn | PD | (52, 4) |
| dnaQ950 | G522->A | Ala 164 Val | D | (2, 55) |
RESULTS
To gain insights into the functional and structural properties of the pol III [epsis] subunit, we have conducted an analysis of a total of 20 dnaQ mutants that were isolated in our laboratory based on the mutator phenotype that they confer. The mutator phenotype presumably reflects the proofreading deficiency they confer during DNA replication. Our analysis involves (i) measurement of the strength of the mutator phenotype, (ii) determination of the DNA sequence changes underlying the mutations, and (iii) assessment of the ability of the mutant proteins to interact with the [alpha] subunit via genetic complementation. In Figure
Further characterization of the dnaQ alleles was achieved by determination of the amino acid sequence changes responsible for each mutator phenotype. Each dnaQ gene was sequenced in its entirety and the observed base changes and resulting amino acid substitutions are presented in Table 1. All of the base changes involved G·C->A·T transitions, consistent with the mutational specificity of hydroxylamine, the mutagen used to create the alleles (31). Three of the mutations involved a tandem base change, but in each case only one amino acid substitution resulted. Amino acid substitutions were found in the putative Exo I and Exo II motifs (underlined) as well as in the region between these two motifs (Fig.
Figure 1. Mutant frequencies for dnaQ mutators. All dnaQ alleles were present in strain NR9601 (Materials and Methods), which also served as dnaQ+ control. Frequencies for Rifr mutations were determined as described in Materials and Methods. Figure 2. The amino acid sequence of [epsis] subunit and changes observed in dnaQ mutator alleles. The amino acid sequence is as reported by Maki et al. (14). The one-letter amino acid code is used. The underlined letters represent amino acids in Exo motif I QIVLDTETTGMNQIG (residues 8-21) and Exo motif II LVIHNAFDIGFMD (residues 95-108) as proposed by Blanco et al. (17). Outlined letters (residues 209-223) represent the Exo III motif as proposed by Blanco et al. (17). The dashed line indicates the entire Exo III[epsis] motif (residues 128-192) as proposed by Barnes et al. (27), while bold letters represent highly conserved residues (Asp129, His162 and Asp167) within the extended motif. Letters above the sequence represent the substitutions found in the dnaQ mutators in this study. Other sequenced dnaQ mutations, not found in our study but observed by Strauss et al. (29), are indicated in parentheses above the sequence. Figure 3. Complementation of dnaQ mutator alleles by dnaQ+. The black bars indicate the level of Rifr mutations in the strains without plasmid, while the gray bars indicate the level of Rifr mutations in the same strain but containing plasmid pSTB101 (dnaQ+). The data illustrate that mutD5 and dnaQ928 are dominant and that dnaQ49 and dnaQ932 are recessive. The results for the other dnaQ alleles are summarized in Table 1. The complementation experiments were performed in the mismatch-repair-defective background (Materials and Methods) to avoid indirect effects via restoration of mismatch repair. Mutant frequency determination was as described in Materials and Methods. Recessive alleles (R) are alleles for which the mutant frequency in the presence of pSTB101 (dnaQ+) was equal to or less than the wild-type level. Dominant (D) alleles are those for which the mutant frequency in the presence of pSTB101 (dnaQ+) fell [le]6-fold and remained >3-fold above the wild-type level. Mutants that did not satisfy both criteria for dominant alleles, but nevertheless remained significantly above the background, were designated partially dominant (PD). Formally, no ready distinction can be made between partially dominant and partially recessive mutants. While the mutator activity of the dnaQ alleles is reflective of the proofreading deficiency that they confer, at least two different, although not exclusive, underlying mechanisms can be envisioned. The deficiency may be catalytic, reflecting the loss of exonuclease activity, or structural, reflecting the loss of binding affinity to the polymerase subunit. To possibly distinguish between these pathways, we performed genetic complementation experiments in which the dnaQ alleles were combined with a copy of the dnaQ+ gene. In such experiments, catalytically-deficient mutants, due to their retained binding abilities, compete with the DnaQ+ protein for insertion into the pol III core and therefore exert a mutator effect even in the presence of the wild-type gene. Such behavior in a complementation experiment is considered (semi)dominant. An example of a dominant dnaQ mutator is mutD5 (38,40). In contrast, recessive dnaQ mutants are those that may still be catalytically proficient, but are impaired in their ability to bind to the [alpha] subunit and therefore do not compete effectively with the wild-type protein. An example of a recessive mutant is dnaQ49 (40). A limitation of this assay is that it allows no straightforward distinction between partially dominant and partially recessive mutants. The dnaQ strains carrying the mutator allele on the chromosome were transformed with a low-copy (one or two per cell) mini-F plasmid, pSTB101, carrying the dnaQ+ gene (Materials and Methods), and the Rifr mutant frequencies were determined. These experiments were performed in the mismatch-repair-defective background to avoid the complications associated with the indirect effects that proofreading deficiencies have on the mismatch repair system through saturation (41). Figure 
DISCUSSION
The current study represents a genetic approach to the analysis of [epsis], the 3->5 exonuclease editing subunit of DNA polymerase III. We attempt to correlate the mutator strength (a measure of proofreading loss) with the amino acid changes of each mutator dnaQ allele. We show that the mutator dnaQ alleles increase Rifr mutant frequencies from 6- to 8000-fold, reflecting the range of proofreading deficiencies suffered by these strains during DNA replication. Interestingly, several of the mutator alleles exhibit mutant frequencies up to 3-fold above the mutD5 level which has been generally considered the strongest known single mutator (39). These new strong mutators contain amino acid substitutions in the conserved Exo I, Exo II or Exo III[epsis] motifs (Figs
Figure 4. Comparison of E.coli [epsis] with the [epsis] subunits of other gram-negative organisms, the DNA polymerase III-associated 3[prime]->5[prime] exonucleases of gram-positive organisms and the RNases T from several organisms. Exo motifs I, II and extended III[epsis] are underlined. Highly conserved residues are shown shaded. Those marked with an asterisk (*) are residues proposed to serve as metal ligands (30). The number in parentheses before the start of the alignment refers to the GenBank number for the first residue. Protein sequences were downloaded from GenBank and aligned by the ClustalW 1.7 program (Baylor College of Medicine at http://dot.imgen.bcm.tmc.edu:9331/multi-align/multi-align.html ). ECOLI, E.coli [epsis]; STYPH, Salmonella typhimurium [epsis]; HIN, Haemophilus influenzae [epsis]; BAP, Buchnera aphidicola [epsis]; BSUB, B.subtilis DNA polymerase III; SAUR, Staphylococcus aureus DNA polymerase III; MGENIT, Mycoplasma genitalium DNA polymerase III; MPNEUMO, Mycoplasma pneumoniae DNA polymerase III; RNT_VPA, Rnase T of Vibrio parahaemolyticus; RNT_ECOLI, Rnase T of E.coli; RNT_HIN, Rnase T of H.influenzae. A more extensive alignment containing 148 additional proteins from more diverse lineages can be found in Moser et al. (30). The mutant frequency data also suggest that there are two distinct groups of mutants, one group exhibiting mutant frequencies 700-8000-fold above the background level; the other group exhibiting 6-20-fold increases in mutant frequency. Within the context of the error catastrophe model, our observation of these two groups of mutators suggests that in the one group the increase in replication errors exceeds the threshold for mismatch repair saturation, whereas in the second group it does not. The combined results provide several important insights into the functional regions of [epsis]. Below, we discuss these data in relation to the proposed Exo motifs and an alignment (Fig. Two mutants were found between Exo motifs I and II (R56W and H66Y). Their mutator strength is only moderate. Interestingly, both R56 and H66 are conserved among the four gram-negative organisms (Fig. Two mutants were found in the Exo II motif, H98Y and D103N. H98Y is a moderate mutator while D103N is very strong. Both are (partially) dominant mutators. The location and properties of these mutants are consistent with the Exo II motif playing an important role in catalysis. H98 and D103 are well conserved among the gram-negative and gram-positive organisms, implying an important role for these residues in the functioning of these 3[prime] exonucleases and RNases T. Based on studies on the corresponding aspartate in pol I Klenow fragment (24,52), D103 is probably another ligand for the divalent metal involved in catalysis. Evidence for an additional structural role of certain Exo II residues is suggested by the strong, but recessive, dnaQ49 mutator (V96G) which also resides in this motif. The recessive nature of dnaQ49 probably suggests that the valine residue is important in maintaining the overall structure of the [epsis] protein. This valine residue is well conserved among the gram-positive and gram-negative organisms and the RNases T. A total of 11 mutants were discovered within the limits of the extended Exo III[epsis] motif (27). However, all our mutants were found in a 17 amino acid stretch (residues 164-180). No mutants were discovered of the conserved residue D129 (nor in any other study), although site-specific mutagenesis of this residue in B.subtilis pol III caused a near-complete loss of exonuclease activity (27). It is possible that a larger collection of mutants would have yielded mutants in this residue, although at this time the importance of this residue in [epsis] remains to be determined. The changes at A164 and D167, which are both highly conserved (Fig. We obtained one mutant in the C-terminal portion of [epsis] (W241ochre), which leads to an [epsis] subunit lacking the three C-terminal residues. Complementation experiments revealed that this mutant (dnaQ932) was fully recessive. Strains containing this allele exhibited Rifr mutant frequencies 15-18-fold above the wild-type level. We suggest, based on the recessive character of the mutation, that this mutator phenotype results from reduced binding of [epsis] to the [alpha] (polymerase) subunit. If correct, this suggests that one, two, or all three of the C-terminal amino acids are important for proper interaction of the [alpha] and [epsis] subunits. That the C-terminal region of [epsis] may represent a separate domain is further suggested by the presence of the Q4 stretch at residues 194-197. Glutamine-rich stretches have been observed at linker regions between domains and are thought to serve as a hinge between domains (53-55). Specifically, the region of DnaQ, residues 190-212, that includes the four glutamine residues has been proposed as a member of the Q-linker family of interdomain linkers (56). The generally good homology between [epsis] and the 3[prime] exonuclease of the gram-positive DNA polymerase IIIs ends at the Q4 stretch (Fig. 
ACKNOWLEDGEMENTS
We thank Iwona Fijalkowska, Jin-Yao Mo and Sean Moore for kindly providing the dnaQ mutator strains used in this study. We also thank Dmitry Gordenin and Polina Shcherbakova for critically reviewing the manuscript.
REFERENCES
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