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Stereochemistry-dependent bending in oligonucleotide duplexes induced by site-specific covalent benzo[a]pyrene diol

R Xu1, B Mao, J Xu

  • 1Chemistry Department, New York University, NY 10003, USA.

Nucleic Acids Research
|June 25, 1995
PubMed

Insights

The tumorigenic benzo[a]pyrene metabolite (+)-anti-BPDE significantly shortens DNA persistence length, while its non-tumorigenic enantiomer does not. This difference is linked to specific (+)-trans BPDE-N2-deoxyguanosyl adducts causing DNA bending.

Area of Science:

  • Environmental Chemistry
  • Molecular Biology
  • DNA Damage and Repair

Background:

  • Polycyclic aromatic hydrocarbons (PAHs) like benzo[a]pyrene are environmental mutagens.
  • Metabolites of benzo[a]pyrene, such as anti-BPDE, can covalently bind to DNA, forming adducts.
  • The stereochemistry of these adducts can influence their biological effects, including DNA structure alterations.

Purpose of the Study:

  • To investigate how the stereochemistry of benzo[a]pyrene metabolite adducts affects DNA structure.
  • To correlate the observed DNA structural changes with the tumorigenicity of different BPDE enantiomers.
  • To understand the mechanism by which BPDE-induced DNA lesions alter DNA persistence length.

Main Methods:

  • Hydrodynamic linear flow dichroism to measure DNA persistence length of modified plasmid DNA.
  • Ligation and gel electrophoresis to study DNA bending induced by site-specific BPDE-deoxyguanosyl adducts in oligonucleotide duplexes.
  • Analysis of four stereochemically isomeric anti-BPDE-N2-deoxyguanosyl adducts.

Main Results:

  • The tumorigenic (+)-anti-BPDE significantly decreased DNA persistence length, while the non-tumorigenic (-)-anti-BPDE had no measurable effect.
  • Only the (+)-trans anti-BPDE-N2-deoxyguanosyl adduct induced significant bending or flexible hinge joints in oligonucleotide duplexes.
  • These stereospecific structural changes correlate with the differential effects of BPDE enantiomers on DNA persistence length.

Conclusions:

  • The stereochemistry of BPDE-DNA adducts is critical in determining DNA structural alterations.
  • The bending induced by specific (+)-trans BPDE-N2-dG adducts explains the reduced persistence length observed with (+)-anti-BPDE modification.
  • This study provides insights into the structure-activity relationship of BPDE adducts and their genotoxic potential.

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