DNA base damage recognition and removal: new twists and grooves

The discoveries of nucleotide excision repair and transcription-coupled repair led by Phil Hanawalt and a few colleagues sparked a dramatic evolution in our understanding of DNA and molecular biology by revealing the intriguing systems of DNA repair essential to life. In fact, modifications of the cut-and-patch principles identified by Phil Hanawalt and colleagues underlie many of the common themes for the recognition and removal of damaged DNA bases outlined in this review. The emergence of these common themes and a unified understanding have been greatly aided from the direct visualizations of repair proteins and their interactions with damaged DNA by structural biology. These visualizations of DNA repair structures have complemented the increasing wealth of biochemical and genetic information on DNA base damage responses by revealing general themes for the recognition of damaged bases, such as sequence-independent DNA recognition motifs, minor groove reading heads for initial damage recognition, and nucleotide flipping from the major groove into active-site pockets for high specificity of base damage recognition and removal. We know that repair intermediates are as harmful as the initial damage itself, and that these intermediates are protected from one repair step to the next by the enzymes involved, such that pathway-specific handoffs must be efficiently coordinated. Here we focus on the structural biology of the repair enzymes and proteins that recognize specific base lesions and either initiate the base excision repair pathway or directly repair the damage in one step. This understanding of the molecular basis for DNA base integrity is fundamental to resolving key scientific, medical, and public health issues, including the evaluation of the risks from inherited repair protein mutations, environmental toxins, and medical procedures.