title: Detection of damaged DNA bases by DNA glycosylase enzymes.
abstract: A fundamental and shared process in all forms of life is the use of DNA glycosylase enzymes to excise rare damaged bases from genomic DNA. Without such enzymes, the highly ordered primary sequences of genes would rapidly deteriorate. Recent structural and biophysical studies are beginning to reveal a fascinating multistep mechanism for damaged base detection that begins with short-range sliding of the glycosylase along the DNA chain in a distinct conformation we call the search complex (SC). Sliding is frequently punctuated by the formation of a transient "interrogation" complex (IC) where the enzyme extrahelically inspects both normal and damaged bases in an exosite pocket that is distant from the active site. When normal bases are presented in the exosite, the IC rapidly collapses back to the SC, while a damaged base will efficiently partition forward into the active site to form the catalytically competent excision complex (EC). Here we review the unique problems associated with enzymatic detection of rare damaged DNA bases in the genome and emphasize how each complex must have specific dynamic properties that are tuned to optimize the rate and efficiency of damage site location.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, WBSB 314, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Friedman
authors.forename: James T
authors.initials: JT
authors.lastname: Stivers
mesh_terms: D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000737:chemistry*; D004260:DNA Repair; D043382:DNA-Formamidopyrimidine Glycosylase / Q000737:chemistry; D029968:Escherichia coli Proteins / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry; D007700:Kinetics; D013379:Substrate Specificity; D014498:Uracil / Q000737:chemistry; D051981:Uracil-DNA Glycosidase / Q000737:chemistry
chemical_list: D029968:Escherichia coli Proteins; C024829:8-hydroxyguanine; D014498:Uracil; D006147:Guanine; D004247:DNA; D045647:DNA Glycosylases; D051981:Uracil-DNA Glycosidase; C479058:oxoguanine glycosylase 1, human; D043382:DNA-Formamidopyrimidine Glycosylase; C468610:DNA-formamidopyrimidine glycosylase, E coli
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