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Related Experiment Videos

Carcinogen-induced frameshift mutagenesis in repetitive sequences.

I B Lambert1, R L Napolitano, R P Fuchs

  • 1Groupe de Cancérogenèse et de Mutagenèse Moléculaire et Structurale, Institut de Biologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, Strasbourg, France.

Proceedings of the National Academy of Sciences of the United States of America
|February 15, 1992
PubMed
Summary

The position of acetylaminofluorene adducts in guanine sequences significantly impacts -1 frameshift mutation frequency in Escherichia coli. DNA repair pathways, particularly nucleotide excision repair, and flanking sequences influence mutagenesis outcomes.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Acetylaminofluorene (AAF) is a chemical mutagen that forms adducts on DNA.
  • Frameshift mutations are insertions or deletions of nucleotides that alter the reading frame of genes.
  • The mutagenic mechanisms of AAF adducts, especially within repetitive sequences, are not fully understood.

Purpose of the Study:

  • To investigate the mutagenic potential of single acetylaminofluorene adducts within guanine-rich sequences.
  • To determine the influence of adduct position and flanking DNA sequences on -1 frameshift mutation induction.
  • To elucidate the role of DNA repair pathways and replication fidelity in AAF-induced mutagenesis.

Main Methods:

  • Construction of plasmids containing single AAF adducts at specific positions within CCCG and CGGGG sequences.

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  • Mutation frequency analysis in Escherichia coli, including repair-proficient and repair-deficient strains (uvrA6 mutant).
  • DNA sequencing to identify the types and locations of mutations induced by AAF adducts.

    • Main Results:

    • The mutagenicity of AAF adducts was highly dependent on their position within guanine runs, with adducts closer to the 3' end being more mutagenic.
    • Mutagenesis was SOS-dependent and significantly reduced in nucleotide excision repair-proficient bacteria compared to repair-deficient mutants.
    • DNA sequencing revealed targeted frameshift mutations within the guanine sequence and semitargeted mutations in the 5' flanking cytosine sequence, particularly when adducts were not at the 3' end of the run.

    Conclusions:

    • The position of an AAF adduct within a guanine sequence dictates its mutagenic potency, with 3'-proximal adducts being more mutagenic.
    • Nucleotide excision repair and SOS response are critical in processing AAF adducts and influencing frameshift mutagenesis.
    • AAF adducts can impair DNA replication fidelity at positions 5' to the lesion, leading to semitargeted frameshift mutations, especially in the presence of repetitive sequences.