Nucleosomal embedding reshapes the dynamics of abasic sites

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Apurinic/apyrimidinic (AP) sites are common DNA lesions repaired by base excision.
• In nucleosomal DNA, AP sites have shorter lifetimes and form more DNA-protein cross-links (DPCs), hindering repair.

Purpose of the Study:

• To investigate the conformational dynamics and repair mechanisms of AP sites within nucleosomal DNA.
• To understand the role of AP site location and histone interactions in DPC formation.

Main Methods:

• All-atom molecular dynamics simulations (microsecond range).
• Analysis of AP sites and tetrahydrofuran analogs within a nucleosome core particle.
• In silico mapping of DNA-protein interactions.

Main Results:

• Deoxyribo-based and tetrahydrofuran-type abasic sites exhibit different behaviors.
• Lesion site location within the nucleosome influences DNA conformation (extrahelicity).
• Spontaneous non-covalent interactions between AP sites and histone tails (H2A, H2B) were identified, prefiguring DPCs.

Conclusions:

• Nucleosomal DNA structure significantly impacts AP site stability and repair.
• Histone tail interactions are crucial in the formation of DNA-protein cross-links.
• In silico findings provide a basis for experimental studies on DPC formation mechanisms.