Correlated target search by uracil-DNA glycosylase in the presence of bulky adducts and DNA-binding ligands

Many proteins specific for rare targets in DNA, such as transcription factors, restriction endonucleases, and DNA repair enzymes, search for their targets by one-dimensional diffusion along DNA. One of these proteins is uracil-DNA glycosylase (Ung), which excises the uracil bases formed by rare events of cytosine deamination. We have studied the ability of Ung to move along DNA with its path hindered by bulky DNA covalent adducts (fluorescein) or ligands blocking the major or minor DNA groove. The fluorescein adduct strongly inhibits translocation only along double-stranded DNA, whereas noncovalently bound ligands partly inhibit DNA cleavage but barely affect translocation. The ability of uracil-DNA glycosylase to search for its targets in the presence of molecules competing for DNA binding may be important for DNA repair in the intracellular environment.