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R F Kimball

Publications and source records attributed to R F Kimball.

At least 19 recordsLinked to original sources
PubMed1987

The development of ideas about the effect of DNA repair on the induction of gene mutations and chromosomal aberrations by radiation and by chemicals.

An historical overview is given of the development of ideas about chromosomal and DNA repair as they relate to the induction of mutations, chromosomal aberrations, and sister-chromatid exchanges by radiations and chemicals. The genetic and molecular bases of the various repair pathways are reviewed whenever possible. Work on both prokaryotes and eukaryotes is included. Mention is made, when deemed appropriate, of major developments in other areas that served as essential background for the repair work, but no attempt is made to cover these background developments in any detail. Near the end, a brief review is given of factors affecting polymerase fidelity. The history is subdivided into approximately 10-year intervals. For the most part, references are to reviews and symposia in which the ideas of the time were brought together. The implications of these findings for some practical problems in genetic toxicology and for our understanding of the maintenance of the genome are discussed at the end.

Chromosome Aberrations↗
PubMed1981

Mutation induction in Haemophilus influenzae by ICR-191. I. Development of a detection system for frameshift mutations.

The investigation of mutagenic mechanisms in Haemophilus influenzae has been confined until now to mutagens that normally produce mainly base pair substitutions. This paper describes the development of a system suitable for detecting frameshift mutations induced by ICR-191. The system involves reversions from thymidine dependence to thymidine independence. Evidence is presented from a comparison of the responses to ICR-191 and to N-methyl-N'-nitro-N-nitrosoguanidine that the system is specific for frameshift mutations. The genetic recombination involved in transformation leads to a marked increase in "spontaneous" reversion of the frameshift mutations but not of the base substitution mutations. Presumably, this is a consequence of mispairing, with consequent change in the number of bases, during the recombination.

Aminacrine↗
PubMed1981

Mutation induction in Haemophilus influenzae by ICR-191. II. Role of DNA replication and repair.

Evidence is presented to show that presumptive frameshift mutations induced in Haemophilus influenzae by ICR-191 are fixed very rapidly, essentially at the time of treatment. DNA synthesis during treatment is essential for fixation, but DNA synthesis after treatment has no effect. The conclusion is drawn that the mutagen acts at the replication fork, possibly to stabilize misannealings arising in association with the discontinuities in the newly synthesized DNA. These results agree with earlier results on Escherichia coli showing that ICR-191 produces peak mutation frequencies in synchronized cultures at times when the replication fork has reached the locus being studied. They are in sharp contrast to the earlier results in H. influenzae with nitroso compounds and hydrazine that suggest these agents produce randomly distributed, reparable pre-mutational damage that still can be fixed (converted to final mutation) for some time after treatment when the replication fork reaches them. No evidence for such persistent pre-mutational lesions was found with ICR-191. A defect in incision appeared to have very little influence on mutation induction by ICR-191 though it caused much more lethality. The interpretation of the mutation data was made somewhat uncertain, however, by an unexplained plating-density effect on the expression of the mutants in this strain. In contrast, incision deficiencies in E. coli and Salmonella typhimurium have been reported to cause a large increase in mutation induction and to allow lesions at some distance from the replication fork to produce mutations.

DNA Repair↗
PubMed1980

Relationship between repair processes and mutation induction in bacteria.

A summary is given of the main repair and replication-associated processes that can influence the induction of mutations by various mutagens in bacteria. These include both constitutive and induced, error-free and error-prone systems. The mutation yield from a treatment with a mutagen can be markedly affected by which of these systems is operating in a given bacterial species or strain. The effect of these systems on mutation induction by ultraviolet light, monofunctional alkylating agents, base analogues, and frameshift mutagens is discussed in some detail. The bearing of these studies on the practical problems of estimating hazards is briefly considered.

Alkylating Agents↗
PubMed1980

A possible mechanism for an interaction between postreplication recombination repair and base misincorporation in mutation induction by N-methyl-N'-nitro-N-nitrosoguanidine in Haemophilus influenzae.

Evidence in previous publications has suggested that treatment with monofunctional alkylating agents such as N-methyl-N'-nitro-nitrosoguanidine (MNNG) results in gaps being left in the DNA synthesized shortly after the treatment. This paper presents further evidence that suggests, though it does not conclusively prove, that there are indeed gaps. It shows that these events increase linearly with MNNG concentration, that they are formed mainly in DNA synthesized during the first hour after treatment, and that only a few are formed at later times. An hypothesis that involves the conversion by recombination repair of a single-strand base substitution, resulting from insertion of an incorrect base opposite an alkylated base, to a double-strand base substitution is proposed. It is suggested that most single-strand substitutions are removed by mismatch repair, leaving the double-strand substitutions as the main source of mutations. This hypothesis predicts that the mutation frequency will increase as the square of the exposure to MNNG, and this seems to be the case, at least at lower exposures at which complicating factors such as lengthened expression time are avoided. It also can explain a number of earlier observations on mutation fixation as detected by transformation. An attempt to show that the non-coding lesions causing the gaps were apurinic sites was unsuccessful.

Centrifugation, Density Gradient↗
PubMed1980

Further studies on the induction of mutation in Haemophilus influenzae by N-methyl-N'-nitro-N-nitrosoguanidine: lack of an inducible error-free repair system and the effect of exposure medium.

Haemophilus influenzae is shown to lack the inducible, error-free repair system for alkylation damage that others have found in Escherichia coli. Prior growth in a low concentration of N-methyl-N'-nitro-N-nitrosoguanidine had only an additive effect on a subsequent brief exposure to a high concentration. Furthermore, chloramphenicol did not significantly modify the mutagenic response. In both respects, H. influenzae differs from E. coli. Experiments carried out in preparation for these tests showed that exposure to N-methyl-N'-nitro-N-nitrosoguanidine in complex growth medium was more effective by about an order of magnitude than exposure in pH 6.0 tris--maelare buffer in inducing mutations, in killing the cells, and in causing strand breaks in the preexisting DNA and gaps in newly synthesized DNA. Thus the effect of the medium is on the amount of initial damage rather than on some special feature of the mutation process. Part but not all of the effect can be accounted for by the difference in pH of the 2 media. The nature of the mutagenic process is the same under the 2 exposure conditions; i.e., reparable pre-mutational damage is produced by the agent and subsequently converted to final mutation by replication. The dose--effect curves have a non-linear initial portion under both exposure conditions, and possible reasons for this non-linearity are discussed.

Chloramphenicol↗
PubMed1978

Evidence against the reversion of mutation in the Haemophilus influenzae phage HP1c1 by preinfection treatment of host cells or phage with MNNG.

N-Methyl-N'-nitrosoguanidine (MNNG) causes reversion of a temperature-sensitive mutation in a bacteriophage of Haemophilus influenzae if exposure to the mutagen takes place after infection but before lysis. However, neither pre-infection treatment of the phage DNA, host cells, or both will cause reversion. The reasons for this are discussed in relation to the somewhat different results in the Escherichia coli lambda phage system and in relation to error-prone repair and replication processes.

Bacteriophages↗
PubMed1978

The role of pre-replication and post-replication processes in mutation induction in Haemophilus influenzae by N-methyl-N'-nitro-N-nitrosoguanidine.

Studies were carried out on the repair and fixation of premutational damage induced in Haemophilus influenzae by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The studies employed a temperature-sensitive DNA elongation mutant (dna9) and its combinations with mutants defective in pyrimidine dimer excision (uvr1, uvr2) and in recombination (rec1). The dna9 mutant is shown to be leaky, allowing about 1% of the normal rate of DNA synthesis at the restrictive temperature. Repair of premutational lesions was detected by a decline in mutation frequency with increasing delay in DNA replication in dna9 at the restrictive temperature. This repair is unaffected by the pyrimidine dimer excision system. Mutation fixation was detected by the ability of DNA from treated and then lysed cells to transfer mutants to recipient cells by transformation. Some fixation occurred at the restrictive temperature but much less than at the non-restrictive temperature suggesting that an appreciable minority of the mutations resulted from lesions introduced near the replication fork but that the majority of mutations arise from lesions introduced at some distance from the fork, perhaps randomly. The DNA synthesized immediately after MNNG treatment is of lower molecular weight than normal and returns to normal with time. This return is blocked in the rec1 mutant, suggesting that recombination is involved. The possible role of this process in MNNG mutagenesis is discussed.

DNA Repair↗
PubMed1978

The relation of repair phenomena to mutation induction in bacteria.

The relation of various processes to mutation induction by radiation and chemicals is discussed for for various species of bacteria. A variety of repair processes have been identified at the molecular level that can eliminate many kinds of potentially mutagenic lesions before they can be converted to final mutation. Fixation often but not always occurs at replication. A number of mutagens, including UV light, ionizing radiation, and a number of chemicals, induce an error-prone process, perhaps a modification of the proof-reading system, that allows bacteria to survive after potentially lethal damage at the expense of making errors. Some mutagens, notably monofunctional alkylating agents and base analogues, produce mutations by other processes. Even in these cases, repair processes play an important role. There is some evidence that error-free as well as error-prone repair processes can be induced. A brief discussion is given of the relation of these findings to the practical problems of hazards estimations.

Alkylating Agents↗
PubMed1977

Evidence that UV-inducible error-prone repair is absent in Haemophilus influenzae Rd, with a discussion of the relation to error-prone repair of alkylating-agent damage.

Haemophilus influenzae Rd and its derivatives are mutated either not at all or to only a very small extent by ultraviolet (UV) radiation, X-rays, methyl methanesulfonate, and nitrogen mustard, though they are readily mutated by such agents as N-methyl-N'-nitro-N-nitrosoguanidine, ethyl methanesulfonate, and nitrosocarbaryl. In these respects H. influenzae Rd resembles the lexA mutants of Escherichia coli that lack the SOS or reclex UV-inducible error-prone repair system. This similarity is further brought out by the observation that chloramphenicol has little or no effect on post-replication repair after UV irradiation. In E. coli, chloramphenicol has been reported to considerably inhibit post-replication repair in the wild type but not in the lexA mutant. Earlier work has suggested that most or all the mutations induced in H. influenzae by NC result from error-prone repair. Combined treatment with NC and either X-rays or UV shows that the NC error-prone repair system does not produce mutations from the lesions induced by these radiations even while it is producing them from its own lesions. It is concluded that the NC error-prone repair system or systems and the reclex error-prone system are different.

Alkylating Agents↗
PubMed1977

Attempts to induce mutations in Haemophilus influenzae with the base analogues 5-bromodeoxyuridine and 2-aminopurine.

Attempts were made to induce mutations in Haemophilus influenzae with the base analogues 5-bromodeoxyuridine and 2-aminopurine. These attempts were unsuccessful. Incorporation studies with BrdUrd showed, in agreement with earlier studies on Escherichia coli, that BrdUrd was discriminated against when dThd was also present but was incorporated to essentially the same extent as dThd when only BrdUrd was present. In this latter case, strands fully substituted with BrdUrd was produced, but survival data suggest that bacteria deriving their DNA by replication on such fully substituted templates were inviable. However, bacteria with about 20% of the thymine substituted with bromouracil were usually viable. No mutations could be detected in the descendants of such bacteria. The reasons for this are discussed and it is concluded that in all probability the replication system in species rarely if every treats incorporated bromouracil as anything except a thymine analogue. The alternative possibility, that the negative results are a consequence of the absence of the reclex (SOS) error-prone repair system in this species, is considered much less likely.

2-Aminopurine↗
PubMed1976

Reversions of two proline-requiring auxotrophs of Haemophilus influenzae by n-methyl-n'-nitro-n-nitrosoguanidine and hydrazine.

New mutation detection systems are described for Haemophilus influenzae. They involve two independently isolated proline auxotrophs which appear to be mutants at different sites in a proline locus (proB) that is very closely linked to a locus (thd) for thymidine requirement. One of the mutants, proB1, appears to revert to prototrophy only by mutations at the locus. The other, proB2, reverts both by mutation at the locus and by unlinked suppressors. The latter account for about 90% of the reversions induced by MNNG and by HZ. The close linkage of proB to thd was used to distinguish between true revertants and suppressors by a transformation test. A comparison was made between the mutation induction kinetics of the different classes of revertants and mutations to novobiocin resistance with MNNG and HZ. The very different induction kinetics for these two mutagens previously reported for the novobiocin resistance system were also found for the proline systems. There were some differences between the detection systems, however, in the frequency of induced mutation relative to the spontaneous frequency and, in one case, in the form of the induction curve. It is concluded that the major features of the induction curves reflect the amount of damage done to DNA and so are general for all systems, but that there are some features which are locus-or site-specific.

DNA, Bacterial↗
PubMed1976

Fixation and loss of hydrazine-induced premutational damage in Haemophilus influenzae.

Premutational damage induced in Haemophilus influenzae by hydrazine appears to be fixed as final mutation only at replication as judged by the transformation assay. Fixation at replication is independent of the rec1 gene, unlike the case with nitrosocarbaryl. Prior to replication premutational damage induced by hydrazine disappears by an unknown process that is not dependent on the presence of a pyrimidine dimer excision system nor on the rec1 gene. Hydrazine does not produce detectable single-strand breaks or alkali-labile sites in the treated DNA nor gaps in DNA newly synthesized after treatment. In these respects it also differs from nitroso compounds. It is concluded that hydrazine acts to produce and altered base, possibly N(4)-aminocytosine, that produces mutations by mispairing at replication rather than by error-prone repair.

Chromosomes, Bacterial↗
PubMed1976

Mutation induction by MNNG in a bacteriophage of Haemophilus influenzae.

Three temperature-sensitive mutants of the Haemophilus influenzae phage HP1c1 were tested for reversion to wild type (ts leads to ts+). Treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) produced revertants at levels up to 0.1% of the total progeny phage from treated lysogens. Cells treated with MNNG after infection with whole ts phage produced progeny phage with similar reversion frequencies, but when the uninfected cells or the phage were treated alone no reversion was induced. Fixation of premutational lesions was shown to occur with no evidence for host-cell DNA synthesis, indicating that phage DNA synthesis may be responsible for fixation of mutation in phage DNA. Evidence is given which shows that prophage DNA replicating by the cells' replicating system after treatment and before induction, produces the same number of revertants per survivor as phage DNA which is replicated outside the host genome. Two of the phage mutants (ts1 and ts2) reverted at similar frequencies, while one of the mutants (ts3) exhibited a much lower induced reversion frequency.

Bacteriophages↗
PubMed1975

Tests for the mutagenic actions of a number of chemicals on Haemophilus influenzae with special emphasis on hydrazine.

A number of chemicals have been tested for their ability to produce novobiocin-resistant mutants in Haemophilus influenzae. Of these, hydrazine (HZ) proved unique because it induced a fairly high incidence of mutation without killing significant numbers of cells at concentrations ranging over nearly four orders of magnitude. Moreover, its dose-effect curve increased very slowly initially and reached a relatively low maximum. It is suggested that HZ may be acting as both a mutagen and an antimutagen in this system. HZ has sometimes been characterized as primarily an inactivating agent rather than as a mutagen. Obviously, quite the opposite is true for H. influenzae. Moreover, a survey of the literature shows that HZ has been used effectively to produce mutations in phage, bacteria, higher plants and Drosophila. There is reason to suspect that it produces mainly single locus mutations rather than chromosomal aberrations, but the amount of information on this point is still very small. The effectiveness of a mutagen can be markedly affected by the criterion of effectiveness used. If a high incidence of mutation with reasonably high cell survival is the criterion, then mutagens that are relatively nontoxic would probably be considered highly effective. In this case, the maximum mutation rate that can be achieved in practice may be controlled either by toxicity or by maxima like the one found for HZ. If, on the other hand, the important criteria are the concentration and exposure time needed to produce a detectable increase in mutation, then some quite toxic mutagens would be considered quite effective even though the maximum mutation that can be produced in practice is low. The first criterion is the one to use in choosing mutagens for detailed analysis of the mutation process, but the second set of criteria may be more suitable for generalizing to other organisms, for example from microorganisms to man, since toxic effects can be quite different in different cell types.

Dose-Response Relationship, Drug↗