Single-Base Lesions and Mismatches Alter the Backbone Conformational Dynamics in DNA

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• DNA damage is linked to diseases such as cancer and aging.
• DNA glycosylases initiate base excision repair by recognizing damaged DNA.
• Altered DNA dynamics may facilitate lesion recognition by repair enzymes.

Purpose of the Study:

• To quantify changes in DNA backbone conformational dynamics caused by single-base lesions and mismatches.
• To investigate the role of these dynamic alterations in DNA repair enzyme binding and specificity.

Main Methods:

• Solution nuclear magnetic resonance (NMR) spectroscopy was employed.
• Quantification of BI-BII backbone conformational dynamics in DNA containing uracil, dihydrouracil, 1,N6-ethenoadenine, and T:G mismatches.

Main Results:

• Stepwise alterations in the %BII and Gibbs free energy (ΔG) of the BI-BII dynamic equilibrium were observed in damaged DNA.
• The dynamic equilibrium shifted towards endothermicity for phosphates near the lesion or mismatch.
• Significant alterations in phosphates correlated with sites critical for DNA repair enzyme binding.

Conclusions:

• Local conformational rearrangements in the DNA backbone are induced by single-base lesions and mismatches.
• These dynamic changes likely play a significant role in the recognition of damaged DNA by repair enzymes.
• Understanding these dynamics can provide insights into DNA repair mechanisms and disease pathogenesis.