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Formation of Covalent DNA Adducts by Enzymatically Activated Carcinogens and Drugs In Vitro and Their Determination by 32P-postlabeling
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Formation of Covalent DNA Adducts by Enzymatically Activated Carcinogens and Drugs In Vitro and Their Determination by 32P-postlabeling

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Enthalpy-entropy contribution to carcinogen-induced DNA conformational heterogeneity

Fengting Liang1, Bongsup P Cho

  • 1Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA.

Biochemistry
|December 8, 2009
PubMed

Insights

Environmental carcinogens like aromatic amines form DNA adducts that can adopt different shapes. This study reveals that entropy, not just enthalpy, dictates the balance between these DNA adduct conformations, influencing cancer risk.

Area of Science:

  • Molecular Biology
  • Chemical Carcinogenesis
  • Structural Biology

Background:

  • DNA adduct formation by aromatic amines is a key step in environmental carcinogenesis.
  • Aromatic amine DNA adducts exist in an equilibrium between major groove (B) and base-displaced stacked (S) conformations.
  • Factors governing this conformational heterogeneity are not well understood.

Purpose of the Study:

  • To investigate the thermodynamic and kinetic factors controlling the B/S conformational equilibrium of DNA adducts.
  • To elucidate the role of enthalpy and entropy in governing DNA adduct conformation.
  • To understand the structural basis of environmental carcinogenesis initiation.

Main Methods:

  • Extensive calorimetry, Nuclear Magnetic Resonance (NMR), and Circular Dichroism (CD) studies.
  • Analysis of model DNA lesions induced by fluorinated 2-aminofluorene (FAF) and 4-aminobiphenyl (FABP).
  • van't Hoff analysis of dynamic (19)F NMR data to determine thermodynamic parameters.

Main Results:

  • Significant differences in enthalpy-entropy compensation were observed between FABP and FAF adducts.
  • FABP adducts exclusively adopt the B conformer with minimal thermodynamic changes.
  • FAF adducts exist as a mixture of B and S conformers, driven by large enthalpy-entropy compensation.
  • Favorable entropy of the S conformer over the B conformer dictates the S/B population ratio at physiological temperatures.

Conclusions:

  • Conformational heterogeneity of DNA adducts is governed by a complex interplay of enthalpy and entropy.
  • Entropy plays a crucial role in determining the population of different DNA adduct conformations.
  • Understanding these thermodynamic principles provides insight into the mechanisms of aromatic amine-induced carcinogenesis.

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