Summary information and primary citation

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X-ray (1.96 Å)
Crystal structure of the post-catalytic nick complex of DNA polymerase lambda with a templating 8-oxo-dg and incorporated da
Burak MJ, Guja KE, Hambardjieva E, Derkunt B, Garcia-Diaz M (2016): "A fidelity mechanism in DNA polymerase lambda promotes error-free bypass of 8-oxo-dG." Embo J., 35, 2045-2059. doi: 10.15252/embj.201694332.
8-oxo-7,8-dihydroxy-2'-deoxyguanosine (8-oxo-dG) has high mutagenic potential as it is prone to mispair with deoxyadenine (dA). In order to maintain genomic integrity, post-replicative 8-oxo-dG:dA mispairs are removed through DNA polymerase lambda (Pol λ)-dependent MUTYH-initiated base excision repair (BER). Here, we describe seven novel crystal structures and kinetic data that fully characterize 8-oxo-dG bypass by Pol λ. We demonstrate that Pol λ has a flexible active site that can tolerate 8-oxo-dG in either the anti- or syn-conformation. Importantly, we show that discrimination against the pro-mutagenic syn-conformation occurs at the extension step and identify the residue responsible for this selectivity. This residue acts as a kinetic switch, shunting repair toward long-patch BER upon correct dCMP incorporation, thus enhancing repair efficiency. Moreover, this switch also provides a potential mechanism to increase repair fidelity of MUTYH-initiated BER.

Cartoon-block schematics in six views (download the tarball)

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