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Ribosomal Assembly Influenced by Growth in the Presence of Streptomycin (Stra Allele/Protein S12/Ribosomes Modified in Vivo/Misreading/T4 Bacteriophage) ROBERT T

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Ribosomal Assembly Influenced by Growth in the Presence of Streptomycin (Stra Allele/Protein S12/Ribosomes Modified in Vivo/Misreading/T4 Bacteriophage) ROBERT T Proc. Nat. Acad. Sci. USA Vol. 70, No. 10, pp. 2762-2766, October 1973 Ribosomal Assembly Influenced by Growth in the Presence of Streptomycin (strA allele/protein S12/ribosomes modified in vivo/misreading/T4 bacteriophage) ROBERT T. GARVIN, ROLAND ROSSET*, AND LUIGI GORINI Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115 Contributed by Luigi Gorini, June 18, 1973 ABSTRACT Translational leakiness (i.e., nonspecific STRAINS AND MEDIA suppression) of nonsense mutants of bacteriophage T4 is increased in cells of certain streptomycin-resistant strains The bacterial strains tested for their ability for nonspecific, previously grown in the presence of streptomycin. Con- ribosomal suppression (measured as translational leakiness of comitantly, ribosomes extracted from these streptomycin- nonsense mutations) are derived from the same Escherichia grown cells possess a high level of misreading. Increased coli B strain Li (argF40, argRl1, no detectable tRNA-sup- suppression ability as well as ribosomes that highly mis- pressors specific for nonsense codons). strA mutant alleles read accumulate with kinetics expected for a constant differential rate of synthesis of a new product induced by were introduced by P1 transduction: strA40 is a streptomycir- drug action. The misreading ribosomes do not contain resistant, moderately restrictive allele permitting expression appreciable amounts of streptomycin and the misreading of phenotypic suppression by streptomycin of argF40 amber property is lost by exposure to high salt concentrations. (our collection number: L1-431). strAl is the most restrictive It is suggested that streptomycin (or dihydrostreptomycin, we have isolated in E. coli B. It or paromomycin) induces a reversible modification in streptomycin-resistant allele 30S subunit assembly without physically participating in gives no detectable suppression by streptomycin of the argF40 the modified structure. The extent of this modification amber (our collection number: L1-401). Strain L190 is a appears dependent upon the strA allele. derivative of Li carrying a strA allele of the drugD type (3) which became streptomycin-independent through a second Under controlled conditions, streptomycin binds directly and Its is streptomycin or paromomycin the site mutation. phenotype specifically to naked 16S RNA, whatever its origin, and when the two drugs are used separately, but it is derived from strepto- resistant drug's failure to bind to 30S subunits sensitive to a mixture of them. The X lysogens are obtained by mycin-resistant cells is apparently due to a masking of the infecting the Li strains with XC1857. They are induced at 420 16S specific site(s) by the mutated S12 protein (1). Moreover, but not at 300. The indicator strain used for titrating T4 16S RNA bound to streptomycin fails to reconstitute in vitro wild-type phage and UGA mutants is CAJ68 (suuGA+). biologically active 30S subunits. Obviously a similar total Cell density is calculated from the optical density (OD) at not occur in vivo failure to assemble active ribosomes does nm with a Lumetron OD of 1.5 cor- in the 480 spectrophotometer. since streptomycin-resistant strains grow normally responds to 2 X 101 cells per ml. presence of streptomycin. It is possible, however, that the Bacteriophage T4 strains are: wild-type D; UGA N65 and drug might be able to interfere in a limited way with the wAl; UAA C410 and C427; and UAG H36 and H39. proper assembly, resulting in functionally altered ribosomes. Medium L contains 10 g of peptone (Difco) and 5 g of yeast we now reexamined With these considerations in mind, have extract (Difco) in 1000 ml of A-N buffer (pH 7). After the an unpublished observation of some years ago, which we were mixture is autoclaved, glucose is added (0.5% final concentra- unable to explain at that time. In studying phenotypic sup- tion). A-N buffer contains (g/liter): K2HPO4, 7; KH2PQ4, 3; pression of T4 nonsense mutants, we observed that strepto- Na citrate 2H20, 0.5; MgSO4c7H2O, 0.1 (pH 7). N+ buffer mycin programs the suppression ability of a strA40 host cell contains (g/liter): NH4Cl, 4.3; MgCl2.6H20, 2.2; Tris, 1.21; before suppression actually occurs. It may be noted that such 2-mercaptoethanol, 0.41 ml (pH 7.8) with HCl. a mechanism is not peculiar to phage infection, but that it becomes evident only with phage because it is possible to RESULTS separate operationally host programming during growth be- Table 1 shows that growth of a bacterial strain in the presence fore infection from actual suppression, which occurs during of streptomycin before infection may increase its ability to phage propagation. support a phage whose propagation depends on overcoming a Our investigation suggests that streptomycin does indeed nonsense translational block. Two actions of streptomycin are interfere with normal ribosomal assembly when a responsive distinguishable. One is exerted during growth before infection S12 mutation is present in the genome and, as a result of this and consists of programming the host efficiency to subse- interference, a functionally altered ribosomal particle is quently translate nonsense mutant phages in the absence of assembled. the drug. The second streptomycin action is exerted directly at the time of phage propagation. The table reports the be- * Present address: Centre National de la Recherche Scientifique, havior of only two UGA mutants but similar results, albeit Centre de Biochimie et de Biologie Moleculaire, 31, Chemin on a smaller scale, are also obtained with the other two types Joseph-Aiguier, 13-Mlarseille, France. of nonsense mutations, i.e., with UAG (H36, H39) and UAA 2762 Downloaded by guest on October 2, 2021 Proc. Nat. Acad. Sci. USA 70 (1978) Ribosomal Modifications In Vivo 2763 (C410, C427) T4 mutants. In the samples presented in the obtained by testing dihydrostreptomycin instead of strepto- table, the programming effect is about 10-times greater than mycin. Moreover, by use of a host strain carrying a strA allele the effect on propagation and this latter effect occurs rela- that confers resistance to both paromomycin and strepto- tively independently from the previous programming. Clearly mycin, the effects of streptomycin and of paromomycin can be the mechanisms underlying the two effects are different and compared. It is found that the effects of the two drugs are the possibility is excluded that the programming effect may identical in pat tern and very similar in amount. consist of a misinterpretation of a trivial artifact due to un- The experiments presented in Figs. 1 and 2 analyze the bound streptomycin not completely washed away. Both kinetics by which the host suppression efficiency increases or streptomycin effects are exerted exclusively on translational decreases when growing cells are shifted from media lacking leakiness of nonsense mutants because growth of wild-type to media containing the drugs and vice versa. It has been phage is indifferent to host pregrowth in streptomycin and to the presence of the drug during phage propagation. The type loor 100 of strA mutation carried in the ribosomes of the host strain Ir plays an essential role in both these streptomycin effects. 0 I// /1 0 75 75 In fact, of the two strA mutants resistant to streptomycin 0 tested, strA40 responds to streptomycin while strAl appears / x indifferent to the drug. This correlates with the known differ- E 50 ., 50k /x /e ence in ability to restrict suppression displayed by these two 2 t ,' /, strA alleles, strA40 being less restrictive than strAl (2). ae 25 251- Finally, results similar to those presented in Table 1 are ,// 2 6 75 100 0 50 75 1i0o-a) TABLE 1. Suppression of T4 UGA mutants by su cells 0 25 5U grown with or without streptomycin before infection 0 1/3 1 2 4 0 1/3 1 2 4 (b) (a) % Sm-ribosomes; (b) cell divisions Host strain used* Fwo. 1. Kinetics by which suppression of efficiency of Li strA40 increases during growth in streptomycin or dihydro- Li streptomycin. Suppression by Li strA40 was tested on T4 strAl mutants C410 ochre (left) and N65 UGA (right). Host pregrowth and phage propagation were at 300 in medium L. Streptomycin or strA40 (Sm Li during dihydrostreptomycin were present for different times during host Sm during (Sm during phage phage pregrowth, but were absent during phage propagation. Different T4 strain host growth) growth) volumes of inoculum, withdrawn from an exponentiaily growing tested pregrowth - + - or + culture reaching OD of 1.5 of Li strA40 (or of its X-lysogen when N65 is tested), were quickly diluted in different volumes of N65 - 2.2 19.9 0.6 warmed medium L, each containing the amount of drug needed for N65 + 149.1 307.6 0.6 a final concentration of 100 ,g/mi. All subcultures (7 ml total vol- coAl - 0.2 0.8 0.02 ume each) were harvested when the same OD of 1.5 was reached coAl + 10.8 19.3 0.02 again, so that each culture went through a different, preestab- Wild type - or + 104 104 104 lished number of cell divisions, but all cells were exactly in the same phase of growth at the moment of phage infection. As a con- T4 bacteriophage strains: N65 and cwAl are UGA mutants trol, the incubation time needed by each subculture to reach OD within and outside the nI region, respectively. E. coli B su- 1.5 was checked and found to be, as expected, the division time strains: Li strA4O and Li strAl are transductants of either strA (30 min) multiplied by the preestablished number of divisions. allele into the same parent. Phage N65 was tested by use of X- Samples of the original undiluted culture were immediately lysogen hosts. Both lysogen and nonlysogen were used with the chilled to 00 and, after addition of the drug, kept in ice through- same results for testing of cAl.
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