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A fidelity mechanism in DNA polymerase lambda promotes error-free bypass of 8-oxo-dG. | LitMetric

AI Article Synopsis

  • 8-oxo-7,8-dihydroxy-2'-deoxyguanosine (8-oxo-dG) can cause mutations by mispairing with deoxyadenine (dA), posing a threat to genomic stability.
  • To prevent such mutations, the body uses DNA polymerase lambda (Pol λ) to remove these mispairs through a process called base excision repair (BER) initiated by MUTYH.
  • The study reveals new crystal structures and kinetic data showing that Pol λ adapts its active site to accommodate 8-oxo-dG and selectively rejects the more dangerous syn-conformation during DNA synthesis, ultimately enhancing the repair process's efficiency and accuracy.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282837PMC
http://dx.doi.org/10.15252/embj.201694332DOI Listing

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