Chemical Biology of Mammalian DNA Repair

Abstract

Damage to the heterocyclic bases of DNA in the genome is mainly corrected by the base excision repair (BER) or nucleotide excision repair (NER) pathways. Base excision repair involves the sequential action of at least four enzymes and is initiated by DNA glycosylases. A lot of progress has recently been made toward elucidating of the molecular mechanisms by which DNA glycosylases recognize damaged bases in DNA and catalyze the cleavage of the N-glycosidic bond between the base and the sugar-phosphate backbone. This advance was brought about by a combination of chemical and biochemical approaches to generate stable complexes of DNA glycosylases bound to their substrates or substrate analogs and X-ray crystallography to determine the structure of these complexes at atomic resolution. Nucleotide excision repair requires the concerted action of 15–18 polypeptides to excise an oligonucleotide of about 30 bases in length containing the damaged residue. The structures of several DNA intermediates in the process are known and the reaction has been recently reconstituted with purified proteins. We know less about the details of how the proteins involved recognize and excise damaged DNA and how specific protein-protein interactions govern the overall process. It is expected that our understanding of nucleotide excision repair will be significantly advanced through the development of novel chemical and cell biological approaches in the near future.