Abstract
Time-resolved molecular snapshots of the bacterial enzyme AlkD reveal an unprecedented mechanism for the recognition and removal of damaged bases in DNA, with implications for cell biology and cancer therapy. See Letter p.254 Not all DNA damage manifests as breaks; for example, ultraviolet light and drugs can modify DNA bases, and these lesions also need to be repaired. Many repair enzymes recognize lesions by 'flipping' bases into a pocket to interrogate whether or not it is damaged. Brandt Eichman and colleagues have now solved multiple crystal structures of the DNA glycosylase AlkD from Bacillus cereus, bound to DNA sequences containing various modified bases. They find, surprisingly, that neither recognition nor catalysis involves base flipping. Instead, AlkD scans the phosphodeoxyribose backbone for increased cationic charge imparted by the alkylated base, and then uses the positive charge to facilitate cleavage of the glycosidic bond. These findings explain AlkD's specificity for cationic lesions.
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