DNA Repair Job Gets Inspected

With the help of a clever cross-linking strategy, chemists at the University of Chicago have determined why one repair protein sticks to fixing up double-stranded DNA damaged by alkylation, whereas its relatives prefer mending single-stranded DNA (Nature 2008, 452, 961). Bacterial AlkB and its human cousin ABH2 both repair alkylated DNA, but no one had been able to sort out why these proteins prefer different DNA substrates. Chuan He and coworkers now present an answer to this mystery based on the crystal structures of AlkB and ABH2 coordinated to a double-stranded DNA bearing an alkylated base. He's team stabilized the weakly interacting DNA-protein complexes via a disulfide cross-link. The structures reveal that ABH2 (right, green), which prefers to repair double-stranded DNA, flips the damaged base (pink) out of the DNA helix (gold) and into its active site while plugging the resulting gap in the DNA with an aromatic phenylalanine "finger." In contrast, AlkB (left, green) dramatically distorts the DNA when it flips the damaged base into its active site. He suggests that AlkB's distortion tactics may account for its preference for single-stranded DNA, which is less rigid than double-stranded DNA.