Mutagenesis vol. 18 no. 4 pp. 355-363,
July 2003
© 2003 UK Environmental Mutagen Society/Oxford University Press
Roles of the RecJ and RecQ proteins in spontaneous formation of deletion mutations in the Escherichia coli K12 endogenous tonB gene
Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai 980–8577, Japan
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Abstract |
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The endogenous tonB gene of Escherichia coli was used as a target for spontaneous deletion mutations which were isolated from recJ– and recQ– cells. Large deletions, due to simultaneous mutations of the trp operon, were also isolated. The rates of tonB mutation were 2.77 x 10–8, 4.13 x 10–8 and 5.00 x 10–8 for rec+, recJ– and recQ– cells, respectively. We analyzed 94 and 99 tonB mutants from the recJ– and recQ– cells, respectively, by sequencing. We found that IS insertion dominated, followed by base substitutions, frameshifts and deletions in both recJ– and recQ– strains. We then analyzed 55 tonB-trp deletions, ranging in size from 5907 to 20 832 bp, from the recJ– strains and 47 tonB-trp deletions, ranging in size from 4959 to 16 390 bp from the recQ– strains. About one-third of tonB-trp deletions from both the recJ– and the recQ– cells were found to have occurred between short sequence repeats at the deletion termini. About one-third of tonB-trp deletions from both mutants showed 2–4 bp repeats in the immediate vicinity of the endpoints, which appeared to indicate no clear association with deletion. The remaining one-third of tonB-trp deletions had no homology at the endpoint. These results were similar to those for the rec+ cells. Hanada and colleagues demonstrated that structually similar rearrangements arising during
bio phage formation (illegitimate recombination) increased in the recQ– strain. To explain this discrepancy, we interpreted as distinctive the mechanism for rearrangement during transducing phage formation which is recQ-dependent and that for deletions formed in chromosomes which is recQ-independent. |
Introduction |
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The molecular mechanisms responsible for generating deletions are not well understood. The role of direct repeats in deletion has been demonstrated by sequence analysis of deletion mutations in Escherichia coli (Farabaugh et al., 1978
; Albertini et al., 1982; Singer and Westlye, 1988; Uematsu et al., 1997) as well as in cells of higher organisms (Nalbantoglu et al., 1986; Ikehata et al., 1989). Two specific models have been proposed that could account for these deletion mutations (Franklin, 1967). One is the slipped mispairing model in which a replication fork slips down a repeated region of the DNA strand during DNA replication, thus leading to deletion mutations. The other is the DNA break-and-joining model. The key event of the latter model is the occurrence of double-strand breaks between the repeats, followed by exonucleolytic erosion and the pairing of exposed complementary sequences. Such rearrangements using short direct repeats for the pairing step have been described in E.coli (Conley et al., 1986; Kong and Masker, 1994).
During the past several years we have developed a system, using the E.coli endogenous tonB gene as a target, to study deletions systematically (Kitamura et al., 1995; Uematsu et al., 1999). The tonB gene is located 4.6 kb in a counterclockwise direction from the trp operon at 
28 min on the linkage map (Figure 1). Thus, a system for the detection of long deletion mutations in the tonB-trp region could be developed (Franklin, 1967; Inselburg, 1967; Ishii and Kondo, 1972; Kitamura et al., 1995). Using this system, we investigated the role of direct repeats in spontaneous deletion and found that almost half of tonB-trp deletions showed 2–4 bp repeats in the immediate vicinity of the deletion endpoints, which seemed to indicate no clear association with deletion. Crossing-over between these homologies can be explained if we assume that the endpoint has one or two extra bases added or deleted (Agemizu et al., 1999; Uematsu et al., 1999; Nagata et al., 2002). Our results further suggested that the slipped mispairing model is more likely to describe the mechanism leading to the deletion mutation in endogenous E.coli genes than the DNA break-and-joining model (Uematsu et al., 1999; Nagata et al., 2002).
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Recently, Ikeda and co-workers suggested that the DNA break-and-joining model is more likely to describe the mechanism leading to illegitimate recombination resulting in
bio transducing phages than the slipped mispairing model (Ukita and Ikeda, 1996; Onda et al., 2001). They further observed that recJ mutations alter the sites and frequency of illegitimate recombination during the formation of bio phages following DNA damage (Ukita and Ikeda, 1996) and recQ mutations show an increase in the frequency of illegitimate recombination during the formation of bio phages (Hanada et al., 1997).
Both RecQ (a 3'
5' DNA helicase) and RecJ (a 5'3' exonuclease specific for single-stranded DNA) belong to the recF recombination pathway (Lovett and Clark, 1984; Nakayama et al., 1985; Lovett and Kolodner, 1989; Umezu et al., 1990). In recombinational repair, RecJ degrades the DNA unwound by RecQ helicase at the double-strand break (Kowalczykowski, 2000). Recent experiments have shown that RecJ together with RecQ is involved in maintaining accurate replication in the presence of DNA damaged by UV by degrading the nascent lagging strand of the replication fork (Courcelle and Hanawalt, 1999). Recently, the genes BLM and WRN, responsible for Bloom’s syndrome and Werner’s syndrome, respectively, have been found to be homologous to the E.coli recQ gene. Cultured cells derived from a patient with Bloom’s syndrome showed an increased rate of sister chromatid exchange and chromosomal aberration (Langlois et al., 1989). Increased rates of somatic mutation, chromosome loss and deletion have been observed in cells having defects in the WRN gene (Scappaticci et al., 1982; Fukuchi et al., 1989; Monnat et al., 1992; Ellis et al., 1995; Yu et al., 1996). In Saccharomyces cerevisiae, sgs1 mutants display higher frequencies of chromosome non-disjunction following mitosis (Stewart et al., 1997). Thus, exonucleases/helicases may help to reduce the number of deletion mutations.
In trying to understand the mechanisms by which deletion mutations formed during DNA replication, we have further characterized the spectra of tonB mutations and tonB-trp region deletions in recQ- and recJ-defective E.coli strains. We found that mutations in recQ and recJ did not produce any increase in the rate of deletion mutations or increase particular types of deletion mutations in the tonB gene or the tonB-trp region compared with wild-type strains. We concluded that RecQ and RecJ function as suppressors of illegitimate recombination during the phage induction process but do not have any role in suppressing deletions formed during DNA replication.
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Materials and methods |
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Bacterial strains and plasmids
The E.coli K12 strains UA2 (recJ::Tn10) and UA3 (recQ::Tn3), which are derivatives of rec+ strain KK1 (Wang et al., 1996
), were used for collecting mutations. KK1 carries the Cmr gene (cat), located 1.6 kb upstream of the tonB gene on the chromosome (Kitamura et al., 1995). The recJ::Tn10 and recQ::Tn3 alleles were derived from strains BIK814 (recJ::Tn10) (Takahashi et al., 1993) and KD2250 (recQ::Tn3) (Nakayama et al., 1994), respectively, by using P1 phage transduction (Ihara et al., 1985). The colicinogenic E.coli strain CA18 carries a colicin B factor (Ishii and Kondo, 1972). Strain XL1-Blue MRF' was used as the host for M13KO7 phage. Plasmids used for cloning the deleted tonB-trp region were pTZ18R and pTZ19R (Amersham Pharmacia Biotech). T1 bacteriophage was included in the colicin plates.
Reagents and media
L broth, L agar and phosphate buffer were prepared as described previously (Najrana et al., 2000; Tanaka et al., 2001). Minimal medium (MM) agar, used for testing for tryptophan auxotrophy, contained M56 salts (Yamamoto, 1985), 0.2% glucose and 1.5% agar with or without tryptophan supplementation (20 µg/ml). Chloramphenicol (Cm) (30 µg/ml), ampicillin (Amp) (50 µg/ml) or tetracycline (Tet) (10 µg/ml) was included, if necessary, in L broth, L agar or MM agar. Enzymes and reagents used for DNA manipulation were purchased from Takara Shuzo (Kyoto, Japan) and Applied Biosystems Inc. (Foster City, CA).
tonB mutant and tonB-trp deletion mutant selection
For the tonB mutation assay, independent KK1, UA2 and UA3 colonies were grown in 2.5 ml of L broth at 37°C overnight. Then, samples of these overnight cultures were plated on colicin plates and colonies were scored as colicin B and T1 phage-resistant (ColBr) mutants after 48 h incubation. Viable cells were scored on L agar after 18 h incubation. ColBr mutations have been shown to be associated with tryptophan auxotrophy (Gratia, 1962; Ishii and Kondo, 1972). The association of tryptophan auxotrophy with ColBr, which we define as a tonB-trp deletion mutant, was checked by re-streaking 100 independent ColBr colonies on MM agar with or without tryptophan. To analyze tonB mutation and tonB-trp deletion mutants, only one ColBr and tryptophan auxotrophic colony was chosen from each colicin plate and MM agar plate with tryptophan, respectively, an approach that ensured that all mutants analyzed were of independent origin. The DNA fragment including the mutant tonB gene or tonB-trp region deletion was amplified by PCR using appropriate primers (Figure 1) from genomic DNA that had been extracted from the mutants. After amplification, the concentration of the amplified DNA was determined from the intensity of the band of proper size on electrophoresis of 1 µl samples on 0.7% agarose gels. Mutant sequences were determined by the dideoxy chain termination method using an automated sequencer.
Mutation rate
Mutation to ColBr was determined for 10 independent cultures of KK1 (rec+), UA2 (recJ) and UA3 (recQ) in 2.5 ml of L broth after overnight growth. For assays scoring ColBr, independent cultures were directly plated onto colicin plates. ColBr colonies were scored after 48 h incubation at 37°C. Total viable cells were determined by serial dilution with phosphate buffer, followed by plating on L agar. Mutation rates, expressed as mutations per cell per generation, were calculated by the method of the median (Lea and Coulson, 1949) using the following formula: mutation rate = M/N, where M is the calculated number of mutation events and N is the mean number of viable cells in the culture. M is solved by interpolation from the experimental determination of ro, the median number of ColBr cells determined among the cultures, by the formula ro = M(1.24 + lnM). The rate with which an overnight culture produces at least one tonB-trp deletion mutant was estimated from the fluctuation test data by assuming that all the tonB-trp deletion mutations occur randomly following a Poisson distribution (Luria and Delbrück, 1943). The mean number of viable cells producing at least one tonB-trp deletion mutant per tube, mN, is given by the equation P(0) = e–mN, where P(0) is the fraction of the tube containing no deletion mutants, m is the deletion mutation rate and N is the mean final cell count per culture. The 
2 test was used to examine differences in the mutation rate among the strains, rec+, recJ– and recQ–. P < 0.05 was regarded as significant.
Retrieving the cat gene with a tonB-trp deletion mutation and sequencing
When a DNA fragment containing the mutant tonB-trp gene was not PCR amplified, the DNA fragment containing the deletion was shotgun-cloned as described previously (Uematsu et al., 1999). In brief, genomic DNA which had been extracted from putative tonB-trp deletion mutants was digested with BamHI and HindIII and ligated into BamHI + HindIII-digested pTZ18R (or pTZ19R) (Figure 1). XL1-Blue MRF' was transformed with the ligation mixture and selected for the Ampr and Cmr phenotypes. The structure of the plasmid DNA, which should contain the tonB-trp deletion, made from between four and six transformants, was identified by EcoRI digestion. When plasmid molecules with the same EcoRI digestion pattern were recovered, one of the plasmids was used for the DNA sequence as described above.
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Results |
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Effect of recJ and recQ on efficiency of tonB mutations
We first measured the spontaneous mutation rate of KK1 (rec+), UA2 (recJ) and UA3 (recQ), which were selected as the ColBr phenotype. The ColBr mutation rate of KK1 was 2.77 x 10–8, of UA2 4.13 x 10–8 and of UA3 5.00 x 10–8 (Table I).
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tonB mutation spectrum
A total of 94 independent ColBr mutated clones from UA2 (recJ–) and 99 from UA3 (recQ–) were collected and used for DNA sequencing. Analysis yielded a mutant sequence in 94 and 99 of these clones, respectively. For comparison, their distributions by class are listed in Table II, along with previously published results from rec+ strain TM31 (Kitamura et al., 1995
). TM31 is not isogenic to UA2 or UA3. The most frequent mutational event in the recJ strain was an insertion sequence (IS) insertion followed by a base substitution, a frameshift and a deletion, in that order. The most frequent mutational event in the recQ strain was an IS insertion followed by a base substitution, a frameshift and a deletion. These spectra did not differ among the rec+, recJ and recQ strains (degree of freedom = 6, 2 = 11.593, P = 0.0717).
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Table III shows the 13 deletions identified from the recJ– strain, among which 11 were at different sites, ranging in size from 3 to 316 bp. The spontaneous deletion rate for UA2 was 5.7 x 10–9 (4.13 x 10–8 x 13/94), which was not different from that observed in the rec+ strain (7.6 x 10–9). Four of these sites were flanked by repeated sequences (Table III, bold letters) of two bases or more, implying a role for direct repeats in deletion. Two of 11 sites showed two- to four-base repeats (Table III, underlined letters) in the immediate vicinity of the deletion endpoints, which seemed to indicate no clear asociation with the deletion. However, cross-over between these homologies can be explained if one assumes that the endpoints have several extra bases added or deleted (Uematsu et al., 1999
). For example, in the case of the deletion of nucleotides 3586–3600 of strain UA3, crossing-over could have occurred within a 3 bp homology, 5'-CCT-3'. However, recombinants contain 5'-T-3', implying that the cross-over occurred asymmetrically within a 3 bp homology. As a result, -CC- bases may have been deleted by a repair process during formation of the deletion, a process called ‘asymmetric cross-over’ (Uematsu et al., 1999). Five deletion sites had no homology at the endpoints.
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Table III also shows five deletion sites identified in the UA3 (recQ–) strain, ranging in size from 4 to 294 bp. The spontaneous deletion rate for UA3 was 3.0 x 10–9 (5.00 x 10–8 x 6/99), which was lower than that observed in the rec+ strain (7.6 x 10–9). One deletion was flanked by a direct repeat, two deletions (nucleotides 3586–3600 and 3514–3517) had a 3 and 4 bp repeat, respectively, in the vicinity of the endpoint, categorized as asymmetric cross-over, and the remaining two had no homology at the endpoints. A deletion at nucleotides 3198–3491 was counted twice in both UA2 and UA3.
We observed 16 and 12 frameshifts among 94 and 99 tonB mutants identified in UA2 and UA3, respectively, giving a frameshift rate of 7.0 x 10–9 and 6.1 x 10–9, respectively. Ten frameshifts in the recJ– strain occurred at runs of two bases or more and five at non-runs (Table IV). Six frameshifts in the recQ– strain occurred at runs and six at non-runs (Table IV). A plus frameshift was found in three among 16 frameshifts in the recJ– strain and once among 12 frameshifts in the recQ– strain. These features of frameshifts in the recJ– and the recQ– strains were essentially the same as those in the rec+ strains (Kitamura et al., 1995). Table II shows that the base substitution rates in recJ– and recQ– were 7.4 x 10–9 and 1.41 x 10–8, respectively.
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Thus, the recJ and recQ mutations do not seem to affect deletion, frameshift and base substitution mutagenesis in the endogenous tonB gene.
tonB-trp deletion mutation in the recJ– and recQ– strains
Although the spontaneous tonB deletion rate and the types of tonB deletion mutations in the endogenous tonB gene of the recJ– and recQ– strains do not differ from those in the rec+ strain, the deletion sample sizes were not large enough. We therefore wanted to compare long deletions of the tonB-trp region in the recJ– and recQ– strains. Actually, Ukita and Ikeda (1996) reported that recJ mutation alters the sites and frequency of rearrangements during formation of the bio transducing phage following DNA damage and Hanada et al. (1997) showed that recQ mutation increases structually similar rearrangements during formation of the bio transducing phage.
We thus determined the spectra of tonB-trp long deletion mutations. To obtain the tonB-trp deletion, the association of ColBr with tryptophan auxotrophy was checked by re-streaking 100 independent ColBr colonies from one colicin plate on MM agar with or without tryptophan. The distance between the tonB gene and trp operon is 4.6 kb (Figure 1). From this analysis, 55 among 647 colicin plates for UA2 (recJ–) and 47 among 473 colicin plates for UA3 (recQ–) gave at least one tryptophan auxotroph. In other words, 592 cultures for recJ– and 426 for recQ– did not give any tryptophan auxotrophs. As shown in Table V, the rate of tonB-trp deletion was 3.67 x 10–11 for the recJ– and 5.23 x 10–11 for the recQ– strains. Although the sample size was small, the KK1 (rec+) strain gave a tonB-trp deletion frequency of 1 x 10–10 (Table V). Thus, as far as the tonB-trp region is concerned, these deletions occurred less frequently in the recJ– and recQ–strains than the rec+ strains.
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Characteristic features in the deletion junctions
The distribution of the tonB-trp deletion endpoints, the sizes of the deletions derived and the sequence characteristics of deletion endpoints from UA2 (recJ–) and UA3 (recQ–) are shown in Tables VI and VII, respectively.
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Among 55 tonB-trp deletions in the recJ– strain, three, nucleotides 1358–13415, 2234–16284 and 3534–19617, occurred twice. Thus, we obtained 52 deletion sites from the recJ– strain, ranging in size from 5907 to 20 832 bp. Nineteen of these sites were flanked by repeated sequences (Table VI, bold letters) of two or more bases. Fifteen of the 52 sites showed 2–4 bp repeats (Table VI, underlined letters) in the immediate vicinity of the endpoints, which we categorized as ‘asymmetric cross-over’. The remaining 18 tonB-trp deletions had no repeats at the endpoints (Table VI).
Among 47 tonB-trp deletions from the recQ– strain, ranging in size from 4959 to 16 390 bp, two, nucleotides 1448–9183 and 3049–9589, occurred twice. Thus, we obtained 45 deletion sites. In these cases, 17 tonB-trp deletions had repeats, 11 had ‘asymmetric cross-over’ and 17 had no homology at the endpoints.
Tables VI and VII clearly indicate that the distribution of deletion endpoints, the size of deletion and the characteristics of endpoint junctions in the tonB-trp deletions were essentially the same between those derived from recJ– and recQ– strains. These features of tonB-trp long deletions in recJ– and recQ– strains were essentially the same as those in the rec+ strain and the recA– strain (Uematsu et al., 1999).
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Discussion |
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In this experiment we have studied spontaneous deletion mutations in the endogenous tonB gene and found neither an increase nor a change in the site of deletions in recJ and recQ strains compared with the rec+ strain.
We first observed 13 tonB deletions among 94 tonB mutants from the recJ strain, giving a deletion rate of 5.7 x 10–9, and six deletions among 99 tonB mutants from the recQ strain, giving a deletion rate of 3.0 x 10–9, which are not different from the rate for rec+ of 5.4 x 10–9 (Table II). The analysis of nucleotide sequences of the tonB deletion mutants revealed that four deletion sites from the recJ strain and one site from the recQ strain had a repeated sequence at the deletion junctions, two sites each for recJ and recQ had an asymmetric cross-over type junction and the remaining five for recJ and two for recQ did not have repeated sequences at the junction (Table III). These features of tonB deletions were essentially the same as those from the rec+ strain (Kitamura et al., 1995). The results therefore indicate that RecJ and RecQ did not play any role in the formation of deletion mutations in the endogenous tonB gene.
Previously it was shown that the formation of bio or pro transducing phages was enhanced by recQ mutation (Hanada et al., 1997). Sequence analysis of these transducing phages indicated that one particular type of hot-spot containing a 9 bp repeat at the rearranged junction is increased by recQ mutation. It has also been indicated that mutation in the recJ gene alters the sites and frequency of rearrangements following UV irradiation (Ukita and Ikeda, 1996).
To solve the difference concerning the effects of RecJ and RecQ between our results and those of Ikeda and colleagues, we next determined the rates and types of tonB-trp long deletions, >4.6 kb in size, and found that the tonB-trp deletion rates of the recJ and recQ strains were not higher than the rate for the rec+ strain (Table V). In these cases we analyzed 55 tonB-trp deletions from the recJ strain (Table VI) and 47 from the recQ strain (Table VII). The analysis of the nucleotide sequences of these long deletions in recJ and recQ did not reveal differences from those in the rec+ strain. About one-third of the tonB-trp deletions had repeated sequences, about one-third were categorized as asymmetric cross-over and the remaining one-third did not have repeated sequences at the deletion junctions. Previously we observed essentially the same distribution of tonB-trp deletions in rec+ as well as recA– strains (Uematsu et al., 1999). Thus, as far as the tonB gene and the tonB-trp region are concerned, RecJ and RecQ as well as RecA do no seem to increase the deletion rate, to alter the deletion sites or to increase or decrease particular types of deletions.
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As mentioned above, Hanada et al. (1997
) observed the effect of a RecQ defect on rearrangement (illegitimate recombination) during the formation of bio transducing phages. The rearrangements during formation are preceded by DNA double-strand breaks because the prophage needs to be excised before joining of the DNA ends. The DNA ends thus formed are processed by nucleases and joined to form recombinant DNA molecules. Thus, Hanada et al. (1997) proposed that the RecQ helicase suppresses illegitimate recombination by causing unwinding of a recombinant intermediate produced by annealing of complementary single-strand ends at a late step in recombination. Consistent with this interpretation, Harmon and Kowalczykowski (1998) showed that RecQ helicase was capable of both disrupting joint molecules and unwinding a variety of partially duplexed DNA substrates.
As mentioned in the Introduction, the formation of deletion mutations can be interpreted by two models (Franklin, 1967); the slipped mispairing model and the DNA break-and-joining model. The formation of rearrangements in transducing phage can be interpreted as the DNA break-and-joining model, as mentioned above, and is suppressed by the function of RecQ helicase. Since the formation of a tonB or tonB-trp deletion is independent of RecQ function (this study) and of RecA function (Uematsu et al., 1999), we argue that deletion mutation in the endogenous gene occurs via a mechanism distinct from the DNA break-and-joining model, i.e. slipped mispairing.
The recent identification of RecQ helicase-like proteins in eukaryotic organisms, including Sgs1 (Saccharomyces cerevisiae), Rqh1 (Shizosaccharomyces pombe) and five human RecQ helicases, namely RecQL1, WRN, BLM, RecQL4 and RecQL5 (Gangloff et al., 1994; Puranam and Blackshear, 1994; Seki et al., 1994; Ellis et al., 1995; Stewart et al., 1997; Kitao et al., 1998, 1999) is of interest. Mutations at the WRN, BLM and RecQL4 loci result in the inherited genetic diseases Werner’s syndrome, Bloom’s syndrome and Rhusmund–Thomson’s syndrome, respectively. The sgs1, WRN and BLM mutants all display similar phenotypes: chromosomal aberrations, chromosomal non-disjunction, hyper-recombination and alterations in DNA replication (Gangloff et al., 1994; Ellis et al., 1995; Watt et al., 1995, 1996; Yu et al., 1996). If these eukaryotic helicases are functional as well as structural homologs of E.coli RecQ helicase, it is possible that they act as suppressors of illegitimate recombination. This possibility is supported by the fact that aberrant recombination events are more frequent in cells from Bloom’s syndrome and Werner’s syndrome patients (Scappaticci et al., 1982; Fukuchi et al., 1989; Monnat et al., 1992; Yu et al., 1996).
Finally, we propose that aberrant chromosomal arrangements, such as chromosomal aberrations and chromosomal non-disjunction in eukaryotic cells and illegitimate recombination in bio transducing phages, are formed by a DNA recombination event which is recQ-dependent, whereas mutations such as tonB deletion and tonB-trp deletion, and probably deletion mutations in eukaryotic cells, are formed by DNA replication slippage, which is recQ-independent.
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Acknowledgements |
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We thank Drs I.Kobayashi (Tokyo University) and H.Nakayama (Kyushu University) for E.coli strains. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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Notes |
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1To whom correspondence should be addressed. Tel: +81 22 217 5054; Fax: +81 22 217 5053; Email: yamamot{at}mail.cc.tohoku.ac.jp
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Received on December 9, 2002; accepted on March 8, 2003.
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