摘要:

AbstractA number of independent critical structural parameters, which have been determined by studies on sedimentation, low angle X‐ray scattering, flow dichroism, flow‐polarized fluorescence, and chemical reactivity, provide the evidence for intercalation of the acridines between two otherwise sequential base pairs, and require the rejection of various alternative hypotheses. The binding requires a local untwisting and extension of the double helix, which is found to be compatible with the normal structural and bonding parameters. The expectation of a substantial alteration in the chemical reactivity of intercalated molecules because of their inaccessibility to electrophilic attack has been verified by reaction rate studies. Study of the relation between viscosity enhancement in dilute DNA solutions and intercalation has been extended using very low shear viscometry. The results agree with the earlier measurements in that the enhancement is observed with the binding of intercalatable cations, while others yield a slight diminution. A pronounced stabilization of the double helix is found, corresponding to a substantially raised thermal transition temperature. Intercalation into polyribonucleotide complexes formed between poly A and poly U renders the double helix substantially more stable than the triple. While intercalation seems to be prerequisite for mutagenicity of the insertion‐deletion type, the acridine structure is not essential, nor are all intercalating molecules muta

ISSN:0095-9898    

DOI:10.1002/jcp.1030640403

出版商:The Wistar Institute of Anatomy and Biology    

年代:1964

数据来源: WILEY

摘要:

AbstractA general method for the interpretation at the molecular level of the genetic products of complex‐acting mutagens is described, using ultraviolet (UV) mutagenesis of phage T4 as an example. The roles of different kinds of intracistronic suppressors in reversion is described. In attempts to modify the course of UV mutagenesis, both caffeine and photoreactivation were found not detectably to affect induced mutation rates, nor was either treatment mutagenic by itself. The mutagenicity of proflavin was shown by test with F‐UdR to be independent of replication, and was also shown not to depend upon the special glucosylation of phage DNA. In experiments testing for a possible role of recombination, proflavin mutagenesis was not augmented by recombination‐stimulating doses of UV. However, the induced mutants did appear to arise in recombinational heterozygotes. Induced mutant clones did not contain the two predicted products of unequal crossing‐over. Possible mechanisms of proflavin mutagenesis were con

ISSN:0095-9898    

DOI:10.1002/jcp.1030640404

出版商:The Wistar Institute of Anatomy and Biology    

年代:1964

数据来源: WILEY

摘要:

AbstractThe spectra of forward‐mutations occurring spontaneously (SP) or induced by X rays (X), nitrous acid (NA), or 2‐aminopurine (AP) at thead‐3Aandad‐3Bloci ofNeurospora crassahave been compared by means of tests for allelic complementation and leakiness. Such tests showed a marked correlation between the percentages of leaky mutants and mutagenic origin. High percentages were found among the NA and AP samples and low percentages among the X and SP samples. The same trend was found with regard to allelic complementation among thead‐3Bmutants. A set of testers derived from a 17‐complon map of thead‐3Bcistron also showed that complementing NA and AP mutants have predominantly nonpolarized complementation patterns with an average complon coverage of 4.7, whereas complementing X and SP mutants have predominantly polarized patterns with an average complon coverage of 13.6. These data provide striking evidence for mutagen specificity inNeurosporaand suggest, furthermore, that there is a correlation between the type of genetic alteration and the type of complement

ISSN:0095-9898    

DOI:10.1002/jcp.1030640405

出版商:The Wistar Institute of Anatomy and Biology    

年代:1964

数据来源: WILEY

ISSN:0095-9898    

DOI:10.1002/jcp.1030640406

出版商:The Wistar Institute of Anatomy and Biology    

年代:1964

数据来源: WILEY

摘要:

AbstractUltraviolet irradiation of DNAin vitroandin vivoresults in the formation of a known structural change — the dimerization of adjacent thymines in the same polynucleotide chain. Many lines of evidence indicate that thymine dimers are responsible for a major part of the lethal, and perhaps mutagenic, effects of ultraviolet irradiation. For example: dimers are split by short‐wavelength ultraviolet and by enzymic action in the presence of visible light; and the decrease in the number of dimers is well correlated with the observed increase in biological activity of DNA or increase in colony‐forming ability of ultraviolet‐irradiated cells. The obvious result of dimer formation is the blockage of DNA synthesis. Studies on anin vitropolymerase system indicate that, in the slow polymerization around thymine dimers, bases other than A are incorporated and that the polymerase product is not complementary to the primer. In cells ofEscherichia coli, on the other hand, the major way of coping with the dimers is to remove them from the bacterial DNA in the form of small oligonucleotides. Such an error‐correcting mechanism would be expected to work for all changes that affect the hydrogen bonding of normal DNA. Mistakes, in a repair mechanism, that are associated with the replacement of structurally incorrect regions in DNA by normal bases will be discussed as possible causes of mu

ISSN:0095-9898    

DOI:10.1002/jcp.1030640407

出版商:The Wistar Institute of Anatomy and Biology    

年代:1964

数据来源: WILEY

摘要:

AbstractThe sensitivity of bacterial species to the lethal effects of radiations and alkylating agents is related to the base composition of their DNA; high guanine and cytosine (GC) content confers increased sensitivity to X rays and mustards and increased resistance to ultraviolet. Preliminary results suggest that differences in average GC content of different markers inBacillus subtilisDNA may be detectable by radiosensitivity analysis. Purine starvation, thymine starvation, or incubation with certain purine and pyrimidine analogues may alter bacterial radiation responsiveness, as reflected in changes in the slope and/or shoulder of dose‐survival curves; the responses differ characteristically with respect to such parameters as time of onset, reversibility, relative expression with X rays versus ultraviolet, oxygen‐dependence, and glycerol‐dependence. Available evidence pertaining to the molecular mechanisms of these radiosensitization phenomena is rev

ISSN:0095-9898    

DOI:10.1002/jcp.1030640408

出版商:The Wistar Institute of Anatomy and Biology    

年代:1964

数据来源: WILEY

摘要:

AbstractIn aromatic hydrocarbons the carcinogenic activity may be quantitatively correlated with the electronic properties of specific regions: the so‐called “K” and “L” regions. In order to be carcinogenic the molecules must possess a “reactive” K region (double bond) and an “unreactive” L region (parapositions). The correlation implies that the interaction leading to carcinogenesis must occur through the K region and involve a strong chemical binding of the type of an addition reaction, possibly subject to steric hindrance. No correlation exists between carcinogenicity of hydrocarbons and their electron transfer properties. The interactions of carcinogenic hydrocarbons with proteins yield results in striking agreement with the theoretical inferences. They indicate the formation of a strong chemical bond between the carcinogens and proteins, through the K region, the reaction involved being an addition. The formation of the complex correlates with the existence of the activity and with its potency. The interactions with the nucleic acids, less explored, may involve hydrophobic and charge transfer forces. In agreement with theoretical predictions this binding is not specific with respect to carcinogens. In other groups of carcinogens (azo‐dyes, aromatic amines, aminofluorene), the situation is to a large extent similar: significant interactions with proteins, ill‐defined interactions with the nucleic acids. The alkylating agents, on the other hand, interact significantly with the nucleic acids. With the possible exception of these last agents, the interaction of molecules with proteins seems to be more directly correlated with the appearance of cancer than their interaction w

ISSN:0095-9898    

DOI:10.1002/jcp.1030640409

出版商:The Wistar Institute of Anatomy and Biology    

年代:1964

数据来源: WILEY

摘要:

AbstractThe chemistry of the reaction of alkylating agents with nucleic acids is briefly reviewed both with respect to the reactive sites and to the destabilization of DNA which results from alkylation. On the basis of these results, mechanisms for mutation by alkylating agents are proposed, and the possible relationships between these and mechanisms for carcinogenesis are discussed. The available evidence suggests that difunctional agents are more effective carcinogens than the corresponding monofunctional agents. This indicates that if carcinogenesis results from mutation then the mutation is most likely to be one resulting from a gross deletion rather than a point change. A study is reported of the binding of a number of H3‐ and C14‐labeled polynuclear aromatic hydrocarbons to the DNA, RNA, and protein of mouse skinin vivoat various times after their application. A firm binding to the cellular constituents was found which persisted in the nucleic acids after extensive purification. Within a limited series of hydrocarbons, a significant positive correlation was observed between the extent of binding of the hydrocarbon to DNA and its carcinogenic power. No such correlation was observed in the binding of hydrocarbon to RNA or protein. Whereas the alkylating agents can react directly with cellular constituents, the hydrocarbons presumably act via reactive metabolites. The nature of these is unknown, but if they were epoxides a fundamentally similar mode of action could be envisaged for both types of carcino

ISSN:0095-9898    

DOI:10.1002/jcp.1030640410

出版商:The Wistar Institute of Anatomy and Biology    

年代:1964

数据来源: WILEY

摘要:

AbstractStudies have been reviewed on the interaction of C14‐ and H3‐labeled carcinogenic hydrocarbons with the tissue constituents of mouse skinin vivo.It has been found that there is a covalent binding between the hydrocarbons and the soluble proteins of mouse skin. Fractionation of these by starch‐gel electrophoresis has shown one characteristic radioactive band of proteins to which the hydrocarbons are bound in a direct quantitative relation to their carcinogenic activity. These proteins resemble electrophoretically the soluble proteins from rat liver to which the hepatocarcinogenie aminoazo dyes are also covalently bound. These proteins are absent from the tumors induced by the hydrocarbons. It has been shown that some papers reporting thein vitrointeraction of carcinogenic hydrocarbons and DNA are in error, and that no binding had actually occurred. In studiesin vivo, no radioactivity could be detected in DNA from mouse skin purified by cesium chloride density gradient centrifugation, following application of highly radioactive hydrocarbons. A possible theory that could explain carcinogenesis by means of a derangement in metabolic control circuitry has been proposed. This theory eliminates the necessity of postulating a direct interaction between the carcinogen and genetic mat

ISSN:0095-9898    

DOI:10.1002/jcp.1030640411

出版商:The Wistar Institute of Anatomy and Biology    

年代:1964

数据来源: WILEY

摘要:

AbstractA large part of the RNA made in presence of azaguanine is in a state of constant turnover. This RNA resembles pulse‐labeled RNA by its chromatographic properties as well. Polyribosomes do not form or they are very labile, indicating improper interaction between ribosomes and messenger RNA. The synthesis of enzymes,e.g., catalase and penicillinase, is completely inhibited under conditions which allow some polypeptide synthesis. This is not due to long‐lived messenger. No abnormal or modified pencillinase could be detected. During restoration by guanosine after azaguanine inhibition the different proteins are not made at the same pace. This may be due to a selective repression caused by accumulated abnormal RN

ISSN:0095-9898    

DOI:10.1002/jcp.1030640412

出版商:The Wistar Institute of Anatomy and Biology    

年代:1964

数据来源: WILEY