Molecular Basis for Uracil-DNA-Glycosylase to Identify DNA Damage in the Nucleosome

The DNA base-excision repair (BER) pathway is initiated by a glycosylase, such as uracil-DNA-glycosylase (UDG), which identifies and removes a wrong base incorporated in the DNA sequence. The very early steps in the identification of the DNA damage are crucial to the correct initiation of the repair chain, and become even more complex when considering the realistic environment of damage to the DNA in the nucleosome. We performed all-atom docking and molecular dynamics computer simulations of the interaction between the glycosylase UDG and a mutated uracil. The model system is a whole nucleosome in which DNA damage is inserted at various positions along the 145-bp sequence. By analyzing an ensemble of $1-\mathrm{\mu s}-\text{long}$ simulation trajectories for each different position, we show that damage recognition by UDG requires very strict structural conditions, unlikely to be matched by purely random search along the DNA. We propose that mechanical deformation of the DNA around the defective sites may help signal the presence of the defect, accelerating the search process.