Mutagenesis originating in site-specific DNA damage

Mitchell, Nancy; Stöhrer, Gerhard

doi:10.1016/0022-2836(86)90254-8

Cited by 20 publications

(13 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutations in the lacI gene from spleen lymphocytes had a much higher proportion of G:C 3 C:G transversion than did lacI mutations from the liver (23% vs. 4%; Table III). As indicated earlier, G:C 3 C:G transversion is the second most common base-pair substitution produced by 2-AAF and its derivatives in some bacterial systems [Mitchell and Stohrer, 1986;Moriya et al, 1988;Hoffmann and Fuchs, 1990]. The mechanism by which 2-AAF adducts produce these mutations or why G:C 3 C:G transversions may be induced in vivo in a tissue-specific (and gene-specific) manner is not known.…”

Section: Comparison Of N-oh-aaf-induced Mutation In the Laci Gene Of mentioning

confidence: 97%

Gene‐ and tissue‐specificity of mutation in Big Blue® rats treated with the hepatocarcinogen N‐hydroxy‐2‐acetylaminofluorene†

Chen

Mittelstaedt

Shelton

et al. 2001

Environ and Mol Mutagen

View full text Add to dashboard Cite

In a previous study, we found that treating transgenic Big Blue rats with the hepatocarcinogen N-hydroxy-2-acetylaminofluorene (N-OH-AAF) produced the same major DNA adduct in the target liver and the nontarget spleen lymphocytes and bone marrow cells, induced lacI mutants in the liver, and induced much lower frequencies of lacI and hprt mutants in spleen lymphocytes. In the present study, sequence analysis was conducted on lacI DNA and hprt cDNA from the mutants, to determine the mutational specificity of N-OH-AAF in the rat. All the mutation spectra from N-OH-AAF-treated rats differed significantly from corresponding mutation profiles from untreated animals (P = 0.02 to P < 0.0001). Although there were similarities among the mutational patterns derived from N-OH-AAF-treated rats (e.g., G:C --> T:A transversion was the most common mutation in all mutation sets), there were significant differences in the patterns of basepair substitution and frameshift mutation between the liver and spleen lymphocyte lacI mutants (P = 0.02) and between the spleen lymphocyte lacI and hprt mutants (P = 0.04). Also, multiplex PCR analysis of genomic DNA from the hprt mutants indicated that 12% of mutants from treated rats had major deletions in the hprt gene; no corresponding incidence of large deletions was evident among lacI mutations. All the mutation profiles reflect the general mutational specificity of the major DNA adduct formed by N-OH-AAF. The differences between N-OH-AAF mutation in the endogenous gene and transgene can be partially explained by the structures of the two genes. The tissue-specificity of the mutation spectra may contribute to targeting tumor formation to the liver. Environ. Mol. Mutagen. 37:203-214, 2001. Published 2001 Wiley-Liss, Inc.

show abstract

Section: Comparison Of N-oh-aaf-induced Mutation In the Laci Gene Of mentioning

confidence: 97%

Gene‐ and tissue‐specificity of mutation in Big Blue® rats treated with the hepatocarcinogen N‐hydroxy‐2‐acetylaminofluorene†

Chen

Mittelstaedt

Shelton

et al. 2001

Environ and Mol Mutagen

View full text Add to dashboard Cite

show abstract

“…The selective incorporation of (AF)G into oligonucleotide duplexes has been accomplished either through direct synthesis (Stohrer et al, 1980;O'Connor & Stohrer, 1985;Mitchell & Stohrer, 1986) or by chemical modification of a single guanosine in a DNA oligomer strand with N-acetoxy-N-(trifluoroacety1)-Zaminofluorene (Johnson et al, 1986;Michaels et al, 1987). The lesion-containing strand can then be paired to the complementary strand to generate duplexes containing either a single (AAF)G or a single (AF)G site.…”

Section: Report Below On a Two-dimensional N M R Study Of The Complemmentioning

confidence: 99%

NMR and computational characterization of the N-(deoxyguanosin-8-yl)aminofluorene adduct [(AF)G] opposite adenosine in DNA: (AF)G[syn].cntdot.A[anti] pair formation and its pH dependence

Norman¹,

Abuaf²,

Hingerty³

et al. 1989

Biochemistry

140

162

View full text Add to dashboard Cite

This paper reports on a combined two-dimensional NMR and energy minimization computational characterization of the conformation of the N-(deoxyguanosyl-8-yl)aminofluorene adduct [(AF)G] positioned across adenosine in a DNA oligomer duplex as a function of pH in aqueous solution. This study was undertaken on the d[C1-C2-A3-T4-C5-(AF)G6-C7-T8-A9-C10-C11].[G12-G13-T14 -A15-G16-A17-G18- A19-T20-G21-G22] complementary undecamer [(AF)G 11-mer duplex]. The modification of the single G6 on the pyrimidine-rich strand was accomplished by reaction of the oligonucleotide with N-acetoxy-2-(acetylamino)fluorene and subsequent deacetylation under alkaline conditions. The HPLC-purified modified strand was annealed with the unmodified purine-rich strand to generate the (AF)G 11-mer duplex. The exchangeable and nonexchangeable protons are well resolved and narrow in the NMR spectra of the (AF)G 11-mer duplex so that the base and the majority of sugar nucleic acid protons, as well as several aminofluorene ring protons, have been assigned following analysis of two-dimensional NOESY and COSY data sets at pH 6.9, 30 degrees C in H2O and D2O solution. The NOE distance constraints establish that the glycosidic torsion angle is syn at (AF)G6 and anti at A17, which results in the aminofluorene ring being positioned in the minor groove. A very large downfield shift is detected at the H2' sugar proton of (AF)G6 associated with the (AF)G6[syn].A17[anti] alignment in the (AF)G 11-mer duplex. The NMR parameters demonstrate formation of Watson-Crick C5.G18 and C7.G16 base pairs on either side of the (AF)G6[syn].A17[anti] modification site with the imino proton of G18 more stable to exchange than the imino proton of G16. Several nonexchangeable aminofluorene protons undergo large downfield shifts as do the imino and H8 protons of G16 on lowering of the pH from neutrality to acidic values for the (AF)G 11-mer duplex. Both the neutral and acidic pH conformations have been defined by assigning the NOE constraints in the [C5-(AF)G6-C7].[G16-A17-G18] segment centered about the modification site and incorporating them in distance constrained minimized potential energy calculations in torsion angle space with the DUPLEX program. A series of NOEs between the aminofluorene protons and the DNA sugar protons in the neutral pH conformation establish that the aminofluorene ring spans the minor groove and is directed toward the G16-A17-G18 sugar-phosphate backbone on the partner strand.(ABSTRACT TRUNCATED AT 400 WORDS)

show abstract

“…As demonstrated in this and in previous studies (43,44), the use of site-specifically modified viral or plasmid DNAs to characterize a mutation spectrum is a powerful technique. Mutagenesis originating from a site-specifically placed 2-acetyl-aminofluorene adduct to guanosine has been described (45,46). The mutations are targeted and consist of transversions or single nucleotide deletions when the modified plasmid is introduced into bacterial or mamalian cells .…”

Section: Class Of Mutation Positionmentioning

confidence: 99%

Mutagenesis induced by site specifically placed 4'-hydroxymethyl-4,5',8-trimethylpsoralen adducts

Piette¹,

Gamper²,

Vorst³

et al. 1988

Nucl Acids Res

View full text Add to dashboard Cite

Closed circular double stranded M13mp19 DNA containing a site-specifically placed HMT (4'-hydroxymethyl-4-5'-8-trimethylpsoralen) monoadduct or crosslink was synthesized in vitro. The damaged DNA were scored for loss of infectivity by transfection into repair proficient or deficient E. coli and into SOS induced E. coli. Mutant phages were detected by the loss of alpha-complementation between the viral and the host Lac Z genes or by the acquisition of resistance to kpn I digestion. Our results indicate that HMT mutagenesis is targeted and that deletion or transversion of the modified thymidine is the predominant sequence change elicited by a monoadduct or a crosslink. Transfection of the monoadducted DNA into a Uvr A deficient strain did not change the mutation pattern but did increase the respective mutation frequencies. Transfection of the crosslinked DNA into a SOS induced host resulted in the appearence of other types of mutations attributable to an increase in both targeted and untargeted mutations.

show abstract

Mutagenesis originating in site-specific DNA damage

Cited by 20 publications

References 15 publications

Gene‐ and tissue‐specificity of mutation in Big Blue® rats treated with the hepatocarcinogen N‐hydroxy‐2‐acetylaminofluorene†

Gene‐ and tissue‐specificity of mutation in Big Blue® rats treated with the hepatocarcinogen N‐hydroxy‐2‐acetylaminofluorene†

NMR and computational characterization of the N-(deoxyguanosin-8-yl)aminofluorene adduct [(AF)G] opposite adenosine in DNA: (AF)G[syn].cntdot.A[anti] pair formation and its pH dependence

Mutagenesis induced by site specifically placed 4'-hydroxymethyl-4,5',8-trimethylpsoralen adducts

Contact Info

Product

Resources

About