The action of mono- and di-functional sulphur mustards on the ribonucleic acid-containing bacteriophage μ2

Shooter, K. V.; Edwards, Paul A.; Lawley, P.D.

doi:10.1042/bj1250829

Cited by 34 publications

(14 citation statements)

References 37 publications

(33 reference statements)

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“…However, there was only a limited correlation between the length of the truncated polypeptide and the length of the RNA message up to the potential alkylation site. Shooter and co-workers (31) were also unable to detect any correlation between the relative number of alkylguanine derivatives (in a RNA-containing bacteriophage p2) and plaque forming ability, and have suggested that other minor alkylation products may be responsible for inactivation of the phage. Furthermore, the response of the ribosome to alkylation sites on RNA is currently not known.…”

Section: Translationmentioning

confidence: 98%

Nitrogen mustard inhibits transcription and translation in a cell free system

1995

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Nitrogen mustard and its derivatives such as cyclophosphamide, chlorambucil and melphalan are widely used anti-cancer agents, despite their non-specific reaction mechanism. In this study, the effect of alkylation by nitrogen mustard of DNA and RNA (coding for a single protein) was investigated using both a translation system and a coupled transcription/translation system. When alkylated DNA was used as the template for coupled transcription and translation, a single translation product corresponding to the 62 kDa luciferase protein was synthesised. Production of the translated product encoded by this template was inhibited by mustard concentrations as low as 10 nM, and 50% inhibition occurred with 30 nM mustard. A primer extension assay employed to verify alkylation sites on the DNA revealed that all guanine residues on the DNA template are susceptible to alkylation by nitrogen mustard. Similarly, when alkylated RNA was used as the template for protein synthesis, the amount of the 62 kDa luciferase protein decreased with increasing mustard concentration and a range of truncated polypeptides was synthesised. Under these conditions 50% inhibition of translation occurred with approximately 300 nM mustard (i.e. approximately 10 times that required for similar inhibition using an alkylated DNA template). Furthermore, a gel mobility shift assay revealed that mustard alkylation of the RNA template results in the formation of a more stable retarded RNA complex. The functional activity of the luciferase protein decreased with alkylation of both the DNA and RNA templates, with a half-life of loss of activity of 1.1 h for DNA exposed to 50 nM mustard, and 0.5 h for RNA exposed to 50 microM mustard. The data presented support the notion that DNA is a critical molecule in the mode of action of mustards.

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Section: Translationmentioning

confidence: 98%

Nitrogen mustard inhibits transcription and translation in a cell free system

1995

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“…The unsaturated keto groups of DNA appear to be functional groups that are attacked by mustard alkylating agents. [10][11][12] Alternatively, compounds such as sodium thiosulfate may reduce the toxicity of mustard by direct chemical reaction with nucleic acid macromolecules. The observation that thiosulfate can be titrated against the active form of mustard gas 13 further suggests that this may be a possible mechanism of action for this type of antidote.…”

Section: Discussionmentioning

confidence: 99%

In vitro effects of anionic sulfur compounds on the spectrophotometric properties of native DNA†

Baskin¹,

Prabhaharan²,

Bowman³

et al. 2001

J. Appl. Toxicol.

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“…In contrast, the exact in vivo consequence of aberrant RNA methylation is unclear. However, pioneering in vivo and in vitro alkylation studies employing RNA phages and polyribonucleic acid, respectively, provided the first insights into RNA damage biology [28][29][30][31]. In an elegant study, Shooter and colleagues related the toxicity of various alkylating agents towards an RNA phage to the formation of 1-meA, 3-meC and probably O 6 -meG, while the quantitatively dominating lesion 7-meG was more harmless [30].…”

Section: Dysfunctionmentioning

confidence: 99%

RNA Base Damage and Repair

Feyzi¹,

Sundheim²,

Westbye³

et al. 2007

CPB

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Elaborate repair pathways counteract the deleterious effects of DNA damage by mechanisms that are understood in reasonable detail. In contrast, repair of damaged RNA has not been widely explored. This may be because aberrant RNAs are generally assumed to be degraded rather than repaired. The reason for this view is well founded, since conserved surveillance mechanisms that degrade abnormal RNAs are thoroughly documented. Numerous proteins and protein-RNA complexes are involved in the metabolism of different RNA species, assuring correct transcription, splicing, posttranscriptional modifications, transport, translation and timely degradation of the molecule. However, like DNA, RNA is under constant attack of various environmental and endogenous agents that damage the molecule, such as alkylating agents, radiation and free radicals. Importantly, many DNA damaging drugs used in cancer therapy also modify RNA, presumably causing delayed or faulty translation. This may result in generation of inactive proteins, dominant negative proteins or toxic protein aggregates. Several lines of evidence indicate RNA repair as a possible cellular defence mechanism to cope with RNA damage. Thus, there are convincing examples of tRNA repair by elongation of truncated forms, and repair of cleaved tRNA by T4 phage proteins. In addition, in vitro repair of aberrant tRNA methylation by a methyl transferase has been reported. Finally, recent reports on repair of chemically methylated RNA by AlkB and a human homologue (hABH3) in vitro and in vivo strengthen the idea of RNA base repair as a cellular defence mechanism.

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The action of mono- and di-functional sulphur mustards on the ribonucleic acid-containing bacteriophage μ2

Cited by 34 publications

References 37 publications

Nitrogen mustard inhibits transcription and translation in a cell free system

Nitrogen mustard inhibits transcription and translation in a cell free system

In vitro effects of anionic sulfur compounds on the spectrophotometric properties of native DNA†

RNA Base Damage and Repair

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