Abstract:The goal of this study is to elucidate the mechanism by which nitrogen mustard, a difunctional alkylating agent, inhibits DNA template activity for RNA synthesis. This inhibition could be due not only monofunctional alkylations, known to hinder RNA synthesis, but also to interand intrastrand bridges formed by difunctional alkylation. DNA from bacteriophage T, and Escherichia coli RNA polymerase provide a well-characterized system for RNA synthesis in vitro. Only 20°/, of the T, genome is transcribed by E . col… Show more
“…The elongation stops can generally be ascribed to inter- and intrastrand cross-links, although some covalent lesions may be bypassed by the bacterial enzyme . These results support the early hypothesis that nitrogen mustard intrastrand and interstrand cross-links are the major lesions responsible for in vitro transcription inhibition .…”
Section: B Nitrogen Mustard and Its
Bis-alkylating
Congenerssupporting
confidence: 76%
“…Different covalent adducts inhibit RNA synthesis to a different extent. While covalent binding of 0.2−0.8 drug molecules of nitracrine, furocoumarin, , or other large aromatic compounds , per 10 3 bases are sufficient to reduce RNA synthesis to 37%, a higher degree of template modification by nitrogen mustard (1.1 drug molecules per 10 3 bases) or methylating , and ethylating 94 agents (10−50 modified bases per 10 3 bases) is required in order to achieve the same result. Generally, bulky adducts inhibit RNA synthesis to a greater extent than small alkylating species.…”
Section: Inhibition Of Total Rna Synthesismentioning
confidence: 99%
“…c Interpolated from two experimental points. d Data from refs and . Other data were calculated for this review.…”
Section: Inhibition Of Total Rna Synthesismentioning
confidence: 99%
“…The former reacts mainly with N7 of G ( 18 ) and, to a lesser extent, N3 of A, while the latter causes ethylation of the oxygen atoms of G or phosphate residues . However, DNA depurination occurring at the alkylation sites complicates the evaluation of data. , More recent experiments lead to the conclusion that N3 methylation of A affects T7 RNA pol although E. coli RNA pol is less sensitive . Both initiation and total RNA synthesis are reduced to a similar extent, and no appreciable changes in RNA chain length are observed at low enzyme/template ratio.…”
Section: A Small Monofunctional Adductsmentioning
confidence: 99%
“…160 These results support the early hypothesis that nitrogen mustard intrastrand and interstrand cross-links are the major lesions responsible for in vitro transcription inhibition. 100 When the reaction is continued for up to several hours, the modified bases are hydrolyzed, and this in turn releases the transcription blockages. 144 The stops which are persistent under these conditions appear to correspond to interstand cross-links occurring between purines in the G-N-C/G-N-C or G-N-T/A-N-C sequences 144 (see also note 32).…”
Section: B Nitrogen Mustard and Its Bis-alkylating Congenersmentioning
where he is now Professor of Biochemistry. His general research interests are in enzymology of nucleic acid and nucleic acids−ligands (especially anticancer drugs) interactions.
“…The elongation stops can generally be ascribed to inter- and intrastrand cross-links, although some covalent lesions may be bypassed by the bacterial enzyme . These results support the early hypothesis that nitrogen mustard intrastrand and interstrand cross-links are the major lesions responsible for in vitro transcription inhibition .…”
Section: B Nitrogen Mustard and Its
Bis-alkylating
Congenerssupporting
confidence: 76%
“…Different covalent adducts inhibit RNA synthesis to a different extent. While covalent binding of 0.2−0.8 drug molecules of nitracrine, furocoumarin, , or other large aromatic compounds , per 10 3 bases are sufficient to reduce RNA synthesis to 37%, a higher degree of template modification by nitrogen mustard (1.1 drug molecules per 10 3 bases) or methylating , and ethylating 94 agents (10−50 modified bases per 10 3 bases) is required in order to achieve the same result. Generally, bulky adducts inhibit RNA synthesis to a greater extent than small alkylating species.…”
Section: Inhibition Of Total Rna Synthesismentioning
confidence: 99%
“…c Interpolated from two experimental points. d Data from refs and . Other data were calculated for this review.…”
Section: Inhibition Of Total Rna Synthesismentioning
confidence: 99%
“…The former reacts mainly with N7 of G ( 18 ) and, to a lesser extent, N3 of A, while the latter causes ethylation of the oxygen atoms of G or phosphate residues . However, DNA depurination occurring at the alkylation sites complicates the evaluation of data. , More recent experiments lead to the conclusion that N3 methylation of A affects T7 RNA pol although E. coli RNA pol is less sensitive . Both initiation and total RNA synthesis are reduced to a similar extent, and no appreciable changes in RNA chain length are observed at low enzyme/template ratio.…”
Section: A Small Monofunctional Adductsmentioning
confidence: 99%
“…160 These results support the early hypothesis that nitrogen mustard intrastrand and interstrand cross-links are the major lesions responsible for in vitro transcription inhibition. 100 When the reaction is continued for up to several hours, the modified bases are hydrolyzed, and this in turn releases the transcription blockages. 144 The stops which are persistent under these conditions appear to correspond to interstand cross-links occurring between purines in the G-N-C/G-N-C or G-N-T/A-N-C sequences 144 (see also note 32).…”
Section: B Nitrogen Mustard and Its Bis-alkylating Congenersmentioning
where he is now Professor of Biochemistry. His general research interests are in enzymology of nucleic acid and nucleic acids−ligands (especially anticancer drugs) interactions.
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