The DNA trackwalkers: Principles of lesion search and recognition by DNA glycosylases

DNA glycosylases, the pivotal enzymes in base excision repair, are faced with the difficult task of recognizing their substrates in a large excess of unmodified DNA. We present here a kinetic analysis of DNA glycosylase substrate specificity, based on the probability of error. This novel approach to this subject explains many features of DNA surveillance and catalysis of lesion excision by DNA glycosylases. This approach also is applicable to the general issue of substrate specificity. We discuss determinants of substrate specificity in damaged DNA and in the enzyme, as well as methods by which these determinants can be identified.