Apurinic/apyrmidinic endonuclease 1 (APE1) plays a central role in DNA repair by cleaving the DNA backbone 5'of AP sites that result from removal of damaged bases. New structural findings on APE1–DNA cocrystals provide insights into how this enzyme binds and cleaves its substrate and how, like one member in an efficient relay team, it coordinates potentially dangerous steps in the base excision repair pathway.

Many different substances produce DNA base damage. Such an onslaught would be ultimately lethal were it not for the ability of mammalian cells to remove much of this damage through base excision repair (BER) 1–5. The importance of this system is illustrated by the fact that a BER deficiency leads to cellular hypersensitivity to certain toxins and to genomic instability and mutations6–8. The main BER pathway in mammalian cells involves removal of a single damaged nucleotide and its replacement with an undamaged base through template directed synthesis to fill the single-nucleotide gap. BER can be initiated (Fig. 1) by any of several damage-specific DNA glycosylases9, 16 that remove damaged bases to produce apurinic/apyrimidinic (AP) sites. AP sites, which can also arise due to spontaneous depurination, are a very common lesion in mammalian cells2. AP sites are also potentially dangerous lesions because they are unstable, can