Skip to main content
Log in

Mutation spectra induced by adozelesin in the supF gene of human XP-A fibroblasts

  • Research Articles
  • Drug Actions
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Adozelesin is a synthetic analog of the antitumor antibiotic, CC-1065, which alkylates N3 of adenine in the minor DNA groove in a sequence-specific manner. Here we tested the mutation spectra induced by adozelesin in the supF gene of human XP-A fibroblasts using a shuttle vector assay. Adozelesin primarily induces mutations via an A → T transversion and a single base insertion. The A → T transversion (43/59) was observed at the adenine alkylation site in the 5′-ATTTA* sequence (A* is the site of alkylation). The single base insertion (5/59) was observed at the 3′-side of the covalently modified adenine in the 5′-CTAAA* sequence. The results of this study suggest that the DNA alkylating sequence of adozelesin influences the type of DNA mutation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Bigger, C. A. H., Ponten, I., Page, J. E., and Dipple, A., Mutational spectra for polycyclic aromatic hydrocarbons in the supF target gene. Mutat. Res., 450, 75–93 (2000).

    CAS  PubMed  Google Scholar 

  • Canella, K. A. and Seidman, M. M., Mutation spectra in supF: approaches to elucidating sequence context effects. Mutat. Res., 450, 61–73 (2000).

    CAS  PubMed  Google Scholar 

  • Hanka, L. J., Dietz, A., Gerpheide, S. A., Kuentzil, S. L. and Martin, D. G., CC-1065 (NSC-298223), a new antitumor antibiotic. Production, in vitro biological activity, microbiological assays, and taxonomy of the producing microorganism. J. Antibiot., 31, 1211–1217 (1978).

    CAS  PubMed  Google Scholar 

  • Harbach, P. R., Zimmer, D. M., Mazurek, J. H., and Bhuyan, B. K., Mutagenicity of antitumor antibiotic CC-1065 and its analogues in mammalian (V79) cells and bacteria. Cancer Res., 48, 32–36 (1988).

    CAS  PubMed  Google Scholar 

  • Hurley, L. H., Reynolds, V. L., Swenson, D. H., Petzold, G. L. and Scahill, T. A., Reaction of the antitumor antibiotic CC-1065 with DNA: Structure of a DNA adduct with DNA sequence specificity. Science, 226, 843–844 (1984).

    Article  CAS  PubMed  Google Scholar 

  • Jin, S-G., Choi, J-H., Ahn, B., O’Connor, T. R., Mar, W., and Lee, C.-S., Excision repair of adozelesin-N3 adenine adduct by 3-methyladenine-DNA glycosylases and UvrABC nuclease. Mol. Cells, 11, 41–47 (2001).

    CAS  PubMed  Google Scholar 

  • Lee, C.-S., Sun, D., Kizu, R., and Hurley, L. H., Determination of the structural feature of (+)-CC-1065 that are responsible for bending and winding of DNA. Chem. Res. Toxicol., 4, 203–213 (1991).

    Article  PubMed  Google Scholar 

  • Lee, C.-S., Pfeifer, G. P., and Gibson, N. W., Mapping of DNA alkylation sites induced by adozelesin and bizelesin in human cells by ligation-mediated polymerase chain reaction. Biochemistry, 33, 6024–6030 (1994).

    Article  CAS  PubMed  Google Scholar 

  • Li, L. H., Kelly, R. C., Warpehoski, M. A., McGovren, J. P., Gebhard, I., and DeKoning, T. F., Adozelesin, a selected lead among cyclopropylpyrroloindole analogs of the DNA-binding antibiotic, CC-1065. Invest. New Drugs, 9, 137–148 (1991).

    Article  CAS  PubMed  Google Scholar 

  • Monroe, T. J. and Mitchell, M. A., In vivo mutagenesis induced by CC-1065 and adozelesin DNA alkylation in a transgenic mouse model. Cancer Res., 53, 5690–5696 (1993).

    CAS  PubMed  Google Scholar 

  • Parris, C. N. and Seidman, M. M., A signature element distinguishes sibling and independent mutations in a shuttle vector plasmid. Gene, 117, 1–5 (1992).

    Article  CAS  PubMed  Google Scholar 

  • Reynolds, V. L., Molineux, I. J., Kaplan, D. J., Swenson, D. H., and Hurley, L. H., Reaction of the antitumor antibiotic CC-1065 with DNA. Location of the site of thermally induced strand breakage and analysis of DNA sequence specificity. Biochemistry, 24, 6228–6237 (1985).

    Article  CAS  PubMed  Google Scholar 

  • Routledge, M. N., Mutation induced by reactive nitrogen oxide species in the supF forward mutation assay. Mutat. Res., 450, 95–105 (2000).

    CAS  PubMed  Google Scholar 

  • Sagher, D. and Struass, B., Insertion of nucleotides opposite apurinic/apyrimidinic sites in deoxynucleic acid during in vitro synthesis: uniqueness of adenine nucleotides. Biochemistry, 22, 4518–4526 (1983).

    Article  CAS  PubMed  Google Scholar 

  • Sarkar, S., Dasgupta, U. B., and Summers, W. C., Errorprone mutagenesis detected in mammalian cells by a shuttle vector containing the supF gene of Escherichia coli. Mol. Cell. Biol., 4, 2227–2230 (1984).

    CAS  PubMed  Google Scholar 

  • Scahill, T. A., Jenson, R. M., Swenson, D. H., Hatzenbuhler, N. T., Petzold, G., Wierenga, W., and Brahme, N. D., An NMR study of the covalent and noncovalent interactions of CC-1065 and DNA. Biochemistry, 29, 2852–2860 (1990).

    Article  CAS  PubMed  Google Scholar 

  • Selby, C. P. and Sancar, Z., ABC exinuclease incises both 5′ and 3′ to the CC-1065-DNA adduct and its incision activity is stimulated by DNA helicase II and DNA polymerase I. Biochemistry, 27, 7184–7188 (1988).

    Article  CAS  PubMed  Google Scholar 

  • Shukla, R., Liu, T., Geacintov, N. E. and Loechler, E. L., The major N2-dG adduct of (+)-anti-B[a]PDE shows a dramatically different mutagenic specificity (predominantly, G→A) in a 5′-CGT-3′ sequence context. Biochemistry, 36, 10256–10261 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Struass, B., Rabkin, S., Sagher, D., and Moore, P., The role of DNA polymerase in base substitution mutagenesis on non-instructional template. Biochimie, 64, 829–838 (1982).

    Article  Google Scholar 

  • Sun, D. and Hurley, L. H., Effect of the (+)-CC1065-(N3-adenine) DNA adduct on in vitro DNA synthesis mediated by Escherichia coli DNA polymerase. Biochemistry, 31, 2822–2829 (1992).

    Article  CAS  PubMed  Google Scholar 

  • Swenson, D. H., Li, L. H., Hurley, L. H., Rokem, J. S., Petzold, G. L., Dayton, B. D., Wallace, T. L., Lin, A. H., and Krueger, W. C., Mechanism of interaction of CC-1065 (NSC 298223) with DNA. Cancer Res., 42, 2821–2828 (1982).

    CAS  PubMed  Google Scholar 

  • Tang, M.-s., Lee, C.-S., Doisy, R., Ross, L., Needham-VanDevanter, D. R., and Hurley, L. H., Recognition and repair of the CC-1065-(N3-adenine)-DNA adduct by the UvrABC nucleases. Biochemistry, 27, 893–901 (1988).

    Article  CAS  PubMed  Google Scholar 

  • Weiland, K. L. and Dooley, T. P., In vitro and in vivo DNA bonding by the CC-1065 analog U-73975. Biochemistry, 30, 7559–7565 (1991).

    Article  CAS  PubMed  Google Scholar 

  • Yoon, J.-H., Smith, L. E., Feng, Z., Tang, M.-s., Lee, C.-S. and Pfeifer, G. P., Methylated CpG dinucleotides are the preferential targets for G to T transversion mutation induced by benzo[a]pyrene diol epoxide in mammalian cells: Similarities with the p53 mutation spectrum in smoking-associated lung cancers. Cancer Res., 61, 7110–7117 (2001).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chong-Soon Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, SY., Pfeifer, G.P. & Lee, CS. Mutation spectra induced by adozelesin in the supF gene of human XP-A fibroblasts. Arch. Pharm. Res. 33, 633–636 (2010). https://doi.org/10.1007/s12272-010-0419-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-010-0419-7

Key words

Navigation