Genetic effects of halogenated thymidine analogs incorporated during thymidylate synthetase inhibition

Lorkiewicz, Z.; Szybalski, Waclaw

doi:10.1016/0006-291x(60)90139-x

Cited by 42 publications

(5 citation statements)

References 7 publications

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“…Finally, BrdU and 5-iodo-2 0 -deoxyuridine at concentrations as high as 1 mM were not toxic for the cell, preventing the estimation of an effect of YjjG in this assay -for these compounds, a low toxicity and no significant increase of the mutation rate despite incorporation into DNA have been observed previously (Lorkiewicz & Szybalski, 1960;Rosner & Yagil, 1970). However, the activity of YjjG towards BrdU was shown in an in vivo DNA incorporation experiment (see below).…”

Section: The Yjjg Mutant Is Sensitive To Noncanonical Pyrimidine Derimentioning

confidence: 91%

TheEscherichia coliprotein YjjG is a house-cleaning nucleotidasein vivo

Titz¹,

Häuser²,

Engelbrecher³

et al. 2007

FEMS Microbiology Letters

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House-cleaning enzymes protect cells from the adverse effects of noncanonical metabolic chemical compounds. The Escherichia coli nucleotide phosphatase YjjG (B4374, JW4336) functions as a house-cleaning phosphatase in vivo. YjjG protects the cell against noncanonical pyrimidine derivatives such as 5-fluoro-2'-deoxyuridine (5-FdUridine), 5-fluorouridine, 5-fluoroorotic acid (5-FOA), 5-fluorouracil, and 5-aza-2'-deoxycytidine. YjjG prevents the incorporation of potentially mutagenic nucleotides into DNA as shown for 5-bromo-2'-deoxyuridine (BrdU). Its enzymatic activity in vitro towards noncanonical 5-fluoro-2'-deoxyuridine monophosphate (5-FdUMP) is higher than towards canonical thymidine monophosphate (dTMP). The closest homolog in humans, HDHD4, does not show a protective effect against noncanonical nucleotides, excluding an involvement of HDHD4 in resistance against noncanonical nucleotides used for cancer chemotherapy. The substrate spectrum of YjjG suggests that its in vivo substrates are noncanonical pyrimidine derivatives, which might also include oxidized nucleobases such as 5-formyluracil and 5-hydroxyuracil.

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Section: The Yjjg Mutant Is Sensitive To Noncanonical Pyrimidine Derimentioning

confidence: 91%

TheEscherichia coliprotein YjjG is a house-cleaning nucleotidasein vivo

Titz¹,

Häuser²,

Engelbrecher³

et al. 2007

FEMS Microbiology Letters

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“…Impairment of photoreactivation of BU-containing bacteria was reported by Greer (J. Gen. Microbiol., in press), and by Lorkiewicz and Szybalski (38). require long term preliminary administration of BUDR, in such a manner as to maintain a level of greater than 2 gg.…”

Section: Discussion and Evamation Of The Theoretical And Practical Immentioning

confidence: 99%

Genetics of Human Cell Lines

Djordjević

Szybalski

1960

The Journal of Experimental Medicine

563

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Strain D98S, a single cell isolate derived from human sternal marrow (1), can be cultivated indefinitely in the presence of 5-bromodeoxyuridine (BUDR) ~ at concentrations below 10 ~g. per ml. Under these conditions BUDR is incorporated into the deoxyribonucleic acid (DNA) component of the cells, partially replacing thymidine. A comparison of the properties of these chemically modified cells with those of the parent cells revealed that a striking increase in radiation sensitivity is associated with BUDR incorporation (2-4). This finding in mammalian cells is analogous to that reported for BUDR-containing bacteriophages (5) and bacteria (6).Several aspects of the incorporation of BUDR and another thymidine analog, 5-iododeoxyuridine (IUDR), including its effect on radiosensitivity, were the subjects of this study. The opportunities afforded by BUDR labeling of DNA synthesized under various conditions were exploited, and the physicochemical and biological properties of such modified DNA were evaluated. Materials and MethodsStrain D98S, culture media, cultivation, plating, staining, colony-counting procedures , and the bromopheno] blue method for protein determination were described earlier (1). DNA was determined by a micro modification of the Burton (7) procedure, using an extract (90°C., 15 minutes, 5 per cent HC104) from defatted, cold 5 per cent perchloric acid-washed cells.

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“…ml.). Lorkiewicz & Szybalski (1960) observed that in the presence of FUDR thymine synthetase was inhibited and a state of thymine deficiency was produced in the cells, and the incorporation of BUDR, the thymidine analogue, into the bacterial DNA can be observed. The substitution of thymidine in the DNA by its brominated analogue (BUDR) renders the cells highly sensitive to the killing action of U.V.…”

Section: -3mentioning

confidence: 92%

“…Table 5 shows that the mutant staphylococci were much more sensitive to heat than was the parent. It is difficult to ascribe a reason for this phenomenon, but it is interesting to note that defects in nucleic acids make bacteria more sensitive to the lethal effect of elevated temperatures (Lorkiewicz & Szybalski, 1960).…”

Section: Eflects Of Other Inhibitorsmentioning

confidence: 99%

Vulnerability of Nucleic Acids in Mutant Staphylococci with Impaired Respiration

Gause¹,

Kochetkova²

1962

Journal of General Microbiology

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SUMMARYMutant staphylococci with impaired respiration, induced by ultraviolet radiation, were used for testing various inhibitors with already known mechanisms of action. Inhibitors of protein synthesis (the tetracyclins) affected the growth of parent and mutant cultures to the same degree.To the inhibitors of cell-wall synthesis (the penicillins) mutant staphylococci were more resistant than the parents; this was related to the altered amino acid composition of cell-wall material in the mutants. On the other hand, the mutants were much more vulnerable than parents to the action of inhibitors which affected the nucleic acids-namely, mitomycin C ( x 50 times), actinomycin C ( x SO), trypaflavine ( x 300), nitrogen mustards ( x 10-20). A specific thymine synthetase inhibitor (5-fluorodeoxyuridine) strongly inhibited the growth of parent staphylococci, but did not at all inhibit the growth of mutants, This points to some deficiency in the enzymic mechanism of synthesis of thymine in the DNA of mutants. Experiments with 5-bromodeoxyuridine suggest that the mutant staphylococci lacked the enzymic mechanism necessary for effective incorporation of halogenated pyrimidines into the DNA precursor pool.

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Genetic effects of halogenated thymidine analogs incorporated during thymidylate synthetase inhibition

Cited by 42 publications

References 7 publications

TheEscherichia coliprotein YjjG is a house-cleaning nucleotidasein vivo

TheEscherichia coliprotein YjjG is a house-cleaning nucleotidasein vivo

Genetics of Human Cell Lines

Vulnerability of Nucleic Acids in Mutant Staphylococci with Impaired Respiration

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