Mechanism of Facilitated Diffusion of DNA Repair Proteins in Crowded Environment: Case Study with Human Uracil DNA Glycosylase

Preserving the genomic integrity is a fundamental requirement, primarily achieved by the DNA repair proteins through their continuous patrolling on the DNA in search of lesions. Human uracil DNA glycosylase (hUNG) is one such DNA repair protein that recognizes uracil in the duplex DNA and excises it using the extrahelical base recognition mechanism. Recent site transfer assay experiments based on full-length hUNG suggest that a crowded environment facilitates its search efficiency, which is enhanced further in the presence of a 93 residue disordered tail associated with its N-terminal. In this study, by performing extensive molecular dynamics simulations with an appropriately tuned model of protein and DNA in the presence of inert crowding agents, we probe the role of cellular crowding and the disordered region in the target search efficiency of the enzyme. Our analysis highlights a complex interplay among the shape of the enzyme, the presence of a disordered tail, and the macromolecular crowding agents that work in harmony to enhance the facilitated diffusion of hUNG protein in a crowded environment. The findings provide novel insights into the in vivo target search mechanism of DNA repair proteins.