In Search of Damaged Bases

Cells continuously face a daunting challenge to find, remove and repair damaged DNA bases within vast excesses of undamaged DNA. Failure to correct these lesions, prior to subsequent rounds of DNA replication, can lead to mutagenic or lethal consequences. In this review, we will attempt to summarize the sequential events by which DNA glycosylases reduce the complexities associated with locating altered bases. For this process to be successful, these enzymes must discriminate between bases that will ultimately be a substrate for catalytic excision and those that escape the repair process. The intent of this review is not to summarize each individual DNA glycosylase or family of related glycosylases, but rather to discuss the topics of damaged DNA target site location, DNA bending, and nucleotide flipping. We will draw upon key examples from the literature to illustrate both the diversity and commonality of the biophysical and biochemical processes that constitute the initiation of base excision repair(BER). Concerning the topics of substrate recognition and the structures of DNA glycosylases and their associated DNA complexes, the reader is referred to Chapter 14. Further, the subject of DNA glycosylasemediated catalysis will not be reviewed within this chapter but the reader is referred to a comprehensive review (1), which is an outstanding compilation and analysis of the literature on DNA glycosylases from a mechanistic chemical perspective.