INTRODUCTION .............................................................. 869 Enzymatic Repair of UV Damage in E. coli ......... .......................... 869 Error-Proof and Error-Prone Pathways of DNA Repair ....... ................. 871 The \"SOS\" Hypothesis: the Regulatory Role of DNA Damage ...... ............ 874 EVIDENCE FOR THE INDUCIBILITY OF ERROR-PRONE REPAIR (\"SOS REPAIR\") ACTIVITY ..................................................... 875 SOS Repair of Bacteriophage DNA ............ ............................... 875 SOS Repair of Bacterial DNA ................ ................................ 876 Evidence from studies of repair-deficient mutants ....... .................... 876 Evidence from studies of postreplication repair ........ ...................... 879 MANIFESTATIONS OF SOS REPAIR AND THEIR SIGNIFICANCE ..... ...... 879 Mutation Frequency Response to Increasing Fluence of UV Radiation ..... ..... 879 The UV Lesion Responsible for Induction of SOS Functions.................... 880 Kinetics of Induction and Decay of SOS Repair Activity ....... ................ 882 Time of Action of SOS Repair in UV Mutagenesis ...... ........................ 882 Cryptic Premutational Lesions Susceptible to SOS Repair ...................... 884 Mutator Effect of SOS Repair on Undamaged DNA ....... ..................... 885 PLASMIDS AND SOS REPAIR ................................................ 886 MECHANISM OF SOS REPAIR ............................................... 886 Mechanism of SOS Repair in Bacteriophage ......... .......................... 886 Mechanism of SOS Repair in Bacteria ........... ............................. 887 IMPLICATIONS OF SOS REPAIR FOR CARCINOGENESIS ................... 888 REGULATION OF SOS REPAIR AND OTHER UV-INDUCIBLE FUNCTIONS . 889 PROTEASES AND THE EXPRESSION OF SOS FUNCTIONS .................. 894 CONCLUSIONS ............................................................... 895 APPENDIX................................................................... 896 LITERATURE CITED ......................................................... 898

Ultraviolet mutagenesis and inducible DNA repair in Escherichia coli.

Publisher Summary This chapter discusses the studies relating to the chemical nature of alkylation, from the products of nucleoside alkylation to in vivo effects of alkylating agents that are oncogenic. The reactions of simple methylating agents with nucleosides, nucleotides, and polynucleotides have also been discussed in the chapter. More recent studies of the mechanism of alkylation by nitroso compounds and ethylating agents have shown that both qualitatively and quantitatively the site of alkylation is a function of both the type of reagent used and the conformation and milieu of the nucleic acid. However, translation of this body of knowledge to an understanding of the biological mechanism of alkylation-induced mutagenesis and carcinogenesis is difficult. Further studies of mutation in picornaviruses or their RNAs would be fruitful since these viral RNAs are also messenger RNAs and are directly translated, whereas in vivo studies, definitive information is still lacking as to whether alkylation of DNA, RNA, or perhaps protein, is the biologically important event.

The chemical effects of nucleic acid alkylation and their relation to mutagenesis and carcinogenesis.

Data on occurrence of nitrate, nitrite and N-nitrosocompounds in food and drinking water, and on total dietary intakes are reviewed. Metabolic, toxicological and epidemiological studies are surveyed and the implications with respect to safety evaluation are addressed. It is concluded that, on the basis of recent long-term animal studies and of clinical experience in man, the current Acceptable Daily Intake (ADI) allocated to nitrate by the Joint FAO/WHO Expert Committee on Food Additives of 0-5 mg/kg body weight/day (expressed as sodium nitrate) might be increased to 0-25 mg/kg body weight/day. Based on similar criteria, the ADI for nitrite would be 0-0.1 mg/kg body weight/day (expressed as sodium nitrite). In view of the known carcinogenicity of N-nitrosocompounds, exposure to these compounds in food should be minimized by appropriate technological means, such as lowering the nitrite concentration in preserved foods to the minimum required to ensure microbiological safety and use of inhibitors of nitrosation like alpha-tocopherol or ascorbic acid. Further work is needed to define the minimal levels of nitrite in foods needed to inhibit outgrowth of Clostridium botulinum and toxin production.

Nitrates, nitrites and N-nitrosocompounds: a review of the occurrence in food and diet and the toxicological implications.

A Glossary of Genetics and Cytogenetics

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present i...

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Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts.

On the basis of experimental data a model of induced mutagenesis is proposed that takes into account the repair of DNA damage by the Rec system. The peculiar feature of the Rec system is the cleavage and resynthesis of long sequences near the recognized DNA damage. Up to 1000–2000 nucleotides are replaced in one act. Therefore a definite probability exists of finding a damaged point on the second strand serving as template. It is believed that at this point no requirements of complementarity exist and that a random substitution can take place. This is the origin of a point mutation (transition, transversion or frameshift). From this model a general formula for the dose-response curve of mutagenesis is deduced which also takes into account the possibility of simultaneously initiated repair on both complementary strands of DNA. The latter leads to a lethal event when the points are situated proximally. This formula fits the observations in different cases studied. Some fundamantal observations such as the absence of mutants from predominant single-strand breaks of DNA chains are readily explained.

Theory of misrepair mutagenesis

1. (1) On the basis of general assumptions a phenomenological theory of inactivation of transforming DNA by various agents (chemical mutagens, UV irradiation, nucleases) is developed. The theory contains one fundamental empirical parameter Z, the number of hits per unit of genetic lenght. All the deductions of the theory are corroborated by experiment. 2. (2) During DNA inactivation by the action of pancreatic DNAase the average number of hits per unit of weight was measured chemically and compared with the number Z found from genetic experiments on the efficiency of transforming DNA. This allows us to calculate the physical dimensions of the scale of the genetic map in Bacillus subtilis and the dimension of a cistron.

Inactivation and mutagenesis on isolated DNA. I. Theory of inactivation of transforming DNA

UV irradiation of Escherichia coli wild-type cells manifested the phenomena of W-reactivation (WR) and W-mutagenesis (WM) of phage lambda irradiated by 60Co gamma-rays in broth. WR of gamma-irradiated phage was half as efficient as that of UV-irradiated phage, although the frequency of c mutations in conditions of WR was about the same in both phages. The xthA and recBrecC sbcB mutants were practically identical with wild-type cells in respect of WR and WM of UV- and gamma-irradiated phage. As in UV-irradiated phage, WR and WM of gamma-irradiated phage were absolutely dependent on the recA+ and lexA+ genes of the host cell. WR and WM required much smaller doses of UV radiation for induction in polA1 and uvrB mutants. The lig-ts mutant, temperature sensitive in polynucleotide ligase, was deficient in WR and WM of UV- and gamma-irradiated phage at the semi-permissive temperature of 37 degrees. The uvrE502 mutant and the allelic recL152 strain were absolutely deficient in WR and WM of gamma-irradiated phage. In UV-irradiated phage WR was reduced, but not eliminated, in the uvrE mutant, and WM was entirely suppressed. This is another example of uncoupling of WR and WM which shows that several repair systems are active in WR but only some of them are mutagenic.

W-reactivation and W-mutagenesis of gamma-irradiated phage lambda.

1 (1) Theoretical concepts are developed on the kinetics of mutagenesis on isolated transforming DNA in vitro  Experimental results are found to be in good agreement with theoretical predictions 2 (2) The efficiency of different mutagens is characterized on the basis of the developed theory All investigated agents can be arranged in the following order according to their mutagenic efficiency: NH 2 OH > HNO 2 > N 2 H 4 > dimethylsulfate > UV irradiation > pH 42

Inactivation and mutagenesis on isolated DNA II. Kinetics of mutagenesis and efficiency of different mutagens

A simple quantitative theory of inactivation of transforming DNA has been formulated. It is based on the idea that genetic recombination of the molecule of transforming DNA with the bacterial genome is possible only, from the point mutation of the gene up to the nearest hit or point of damage on the corresponding DNA molecule. Our data and the data of other authors on the kinetics of inactivation by HNO2 or U.V. light or both are consistent with these theoretical predictions. Theoretical predictions were made concerning the extent of reactivation by fusion mid annealing of damaged DNA with a diluting genetically inactive DNA. These estimates have been reasonably confirmed by our experimental results.

S.E. Bresler

Papers

Theory of misrepair mutagenesis

Inactivation and mutagenesis on isolated DNA. I. Theory of inactivation of transforming DNA

W-reactivation and W-mutagenesis of gamma-irradiated phage lambda.

Inactivation and mutagenesis on isolated DNA II. Kinetics of mutagenesis and efficiency of different mutagens

Theory of inactivation and reactivation of transforming DNA