DNA base sequence effects on bulky lesion-induced conformational heterogeneity during DNA replication

Area of Science:

• Chemical Biology
• Structural Biology
• Molecular Biology

Background:

• 4-Aminobiphenyl (ABP) and 2-aminofluorene (AF) are known carcinogens that can adduct DNA.
• Understanding how these adducts affect DNA structure and function is crucial for assessing their biological impact.

Purpose of the Study:

• To investigate the conformational effects of ABP and AF adducts at specific guanine (G) positions within a DNA duplex.
• To elucidate how sequence context and lesion properties influence DNA conformation and stability.

Main Methods:

• Synthesis and characterization of DNA duplexes containing ABP or AF adducts at G1 and G2 positions.
• Conformational analysis using biophysical techniques to determine the population of different DNA conformers (B-type and stacked).

Main Results:

• ABP modification at G1 yielded a mixture of B-type (67%) and stacked (33%) conformers, while modification at G2 exclusively produced the B-type conformer.
• AF modification resulted in different B:S ratios depending on the position (G1: 25%:75%, G2: 83%:17%).
• Conformational preferences are dictated by a balance of stabilizing (hydrogen bonding, stacking) and destabilizing (solvent exposure) forces, influenced by lesion planarity.

Conclusions:

• The sequence context significantly modulates the conformational outcomes of DNA adducts.
• The relative stability of conformers is context-dependent, with implications for both duplex and single-strand/double-strand (ss/ds) junction stability.
• ABP adducts exhibit stronger strand binding affinity at the ss/ds junction compared to AF adducts, highlighting distinct biological consequences.