DNA repair efficiency is critically dependent on DNA glycosylases, which perform a discriminating search for DNA lesions, damage-specific base extrusion and lesion removal. First, we elucidated the base extrusion mechanism of <i>Bacillus cereus</i> AlkD glycosylase. Unlike most glucosylases, AlkD does not directly expel the alkylated lesion, relying instead on backbone contacts to extrude the lesion's base-pairing partner. We determined a minimum energy path (MEP) for flipping out a 3-methyl adenine base by AlkD using a chain-of-replicas path optimization method. We also computed a potential of mean force (effective free energy profile) along this MEP. We show that lesion extrusion relies on DNA sculpting by the rigid AlkD scaffold. The process involves two steps characterized by low free energy barriers and a stable intermediate. We contrast this strategy to base extrusion by thymine DNA glycosylase (TDG). Computing pathways for 5-carboxycytosine base extrusion by TDG, we show a different mechanism wherein reorganization of both the glycosylase and DNA takes place.

Damage recognition and base extrusion strategies of DNA repair glycosylase enzyme

251st National Meeting (2016)

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