Mutagenic consequences of the incorporation of 6-thioguanine into DNA

Uribe-Luna, Sonia; Quintana-Hau, Juan D; Maldonado-Rodrı́guez, Rogelio; Espinosa-Lara, Mercedes; Beattie, Kenneth L.; Farquhar, David; Nelson, J. Arly

doi:10.1016/s0006-2952(97)00200-1

Cited by 26 publications

(21 citation statements)

References 11 publications

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“…27 In this scenario, DNA repair occurs in situations that would normally induce an apoptosis response, leading to the accumulation of mutations. 28 Notably, we also found a significant association between mutation detection and exposure to 6-Thioguanine, a drug that is mutagenic because of mispairing with thymine after incorporation into DNA, 29 while patients with exposure to other cytotoxic drugs, including cytarabine and topoisomerase II inhibitors, were not at increased risk. Because the number of patients exposed to 6-Thioguanine was small, this finding should be interpreted with caution.…”

Section: Discussionmentioning

confidence: 50%

High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy

Willis

Lange

Demehri

et al. 2005

Blood

285

238

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Mutations in the kinase domain (KD) of BCR-ABL are the leading cause of acquired imatinib resistance. In some cases, identical mutations were detected at relapse and in pretherapeutic specimens, consistent with selection of resistant clones in the presence of drug. However, the incidence of KD mutations in imatinibnaive patients, irrespective of response to therapy, is unknown. We studied mutation frequency in 66 patients with chronic myelogenous leukemia (CML), using cDNA sequencing and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) assays for 8 common mutations. Thirteen patients were positive by ASO-PCR only, 1 by ASO-PCR and sequencing, and 1 by sequencing only (overall frequency, 22.7%). T315I was most frequent (12% of patients). Eleven of the 14 patients with positive ASO-PCR had follow-up samples available for sequencing. Wild-type sequence was detected in 6 of 11, 2 different mutations in 1 of 11, and identical mutations in 4 of 11 patients, 2 of whom had achieved major cytogenetic response. In multivariate analysis mutation detection was associated with clonal cytogenetic evolution, exposure to 6-Thioguanine, and a low platelet count, but not with response to imatinib, event-free survival, and overall survival. KD mutants present at low levels do not invariably lead to relapse, and additional factors are required to induce a fully drug-resistant phenotype. (Blood. 2005; 106:2128-2137)

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Section: Discussionmentioning

confidence: 50%

High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy

Willis

Lange

Demehri

et al. 2005

Blood

285

238

View full text Add to dashboard Cite

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“…Given the above-noted properties, the spontaneous mutation rates of the ES cells were examined by using the surrogate property of resistance selection against the antileukemic agent 6-thioguanine (33,34). This purine analogue induces its lethal effect as a result of its incorporation into DNA.…”

Section: -Thioguanine-resistant Colonies Arise More Frequently From mentioning

confidence: 99%

A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity

Lebel

Leder

1998

Proc. Natl. Acad. Sci. U.S.A.

278

194

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Werner syndrome (WS) is an autosomal recessive disorder characterized by genomic instability and the premature onset of a number of age-related diseases. The gene responsible for WS encodes a member of the RecQ-like subfamily of DNA helicases. Here we show that its murine homologue maps to murine chromosome 8 in a region syntenic with the human WRN gene. We have deleted a segment of this gene and created Wrn-deficient embryonic stem (ES) cells and WS mice. While displaying reduced embryonic survival, live-born WS mice otherwise appear normal during their first year of life. Nonetheless, although several DNA repair systems are apparently intact in homozygous WS ES cells, such cells display a higher mutation rate and are significantly more sensitive to topoisomerase inhibitors (especially camptothecin) than are wild-type ES cells. Furthermore, mouse embryo fibroblasts derived from homozygous WS embryos show premature loss of proliferative capacity. At the molecular level, wild-type, but not mutant, WS protein copurifies through a series of centrifugation and chromatography steps with a multiprotein DNA replication complex.

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“…These studies were later confirmed by the observation that a S6G•C pair has a greater degree of mobility and is marginally less stable than a normal G•C pair (25,26). The comparative stability of an S6G•T mismatch to that of a G•T mismatch or a S6G•C pair is difficult to predict, but, owing to the absence of a strong mutagenic effect for S6G (16), it is likely that the pairing with cytosine will be more stable.…”

Section: Introductionmentioning

confidence: 99%

Effect of 6-thioguanine on the stability of duplex DNA

Bohon

2005

Nucleic Acids Research

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The incorporation of 6-thioguanine (S6G) into DNA is a prerequisite for its cytotoxic action, but duplex structure is not significantly perturbed by the presence of the lesion [J. Bohon and C. R. de los Santos (2003) Nucleic Acids Res., 31, 1331–1338]. It is therefore possible that the mechanism of cytotoxicity relies on a loss of stability rather than a pathway involving direct structural recognition. The research described here focuses on the changes in thermodynamic properties of duplex DNA owing to the introduction of S6G as well as the kinetic properties of base pairs involving S6G. Replacement of a guanine in a G•C pair by S6G results in ∼1 kcal/mol less favorable Gibbs free energy of duplex formation at 37°C. S6G•T and G•T mismatch-containing duplexes have almost identical Gibbs free energy at 37°C, with values ∼3 kcal/mol less favorable than that of the control. Base pair stability is affected by S6G. The lifetime of the normal G•C base pair is ∼125 ms, whereas that of the G•T mismatch is below the detection limit. The lifetimes of S6G•C and S6G•T pairs are ∼7 and 2 ms, respectively, demonstrating that, although S6G significantly decreases the stability of the pairing with cytosine, it slightly increases that of a mismatch.

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Mutagenic consequences of the incorporation of 6-thioguanine into DNA

Cited by 26 publications

References 11 publications

High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy

High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy

A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity

Effect of 6-thioguanine on the stability of duplex DNA

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