DNA polymerase lambda (Pol ?) is a family X DNA polymerase involved in the repair of DNA double strand breaks during non-homologous end joining. In addition, Pol ? has been shown to be key for the error-free bypass of oxidative damage: it is involved in the MutYH-dependent repair of 7,8-dihydro-8-oxoguanine (8-oxodG)/dA mispairs. 8-oxodG is an abundant oxidative lesion that is highly mutagenic, because it promotes the misincorporation of dAMP during DNA replication. Indeed, most polymerases preferentially incorporate dAMP opposite 8-oxodG. In sharp contrast, Pol ? is capable of error-free bypass of 8-oxodG and preferentially extends 8-oxodG/dC pairs. Both properties are thought to be key to its role in the error-free bypass of 8-oxodG. In order to understand the mechanistic basis of this behavior, we have studied the structural characteristics of Pol ? that facilitate this unique behavior. Taking advantage of the fact that the catalytic cycle of Pol ? has been structurally characterized in detail,we have obtained crystal structures of Pol ? in complex with different DNA substrates that capture the polymerase in different steps during bypass of this oxidative lesion. These structures allow us to identify the structural features that allow this polymerase to participate in the error-free bypass of 8-oxoG.

Bypass of oxidative damage by human DNA polymerase lambda

248th National Meeting (2014)

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