The recognition and removal of damaged bases in the genome is the province
of a highly specialized assemblage of enzymes known as DNA glycosylases. In
recent years, structural and mechanistic studies have rapidly moved forwar
d such that in some cases, the high-resolution structures of all stable com
plexes along the reaction pathway are available. In parallel, advances in i
sotopic labeling of DNA have allowed the determination of a transition stat
e structure of a DNA repair glycosylase using kinetic isotope effect method
s. The use of stable substrate analogs and fluorescent probes have provided
methods for real time measurement of the critical step of damaged base fli
pping. Taken together, these synergistic structural and chemical approaches
have elevated our understanding of DNA repair enzymology to the level prev
iously attained in only a select few enzymatic systems. This review summari
zes recent studies of the paradigm enzyme, uracil DNA glycosylase, and disc
usses future areas for investigation in this field. (C) 2001 Elsevier Scien
ce.