5III

Crystal structure of the pre-catalytic ternary complex of DNA polymerase lambda with a templating 8-oxo-dG and an incoming dATP

Summary for 5III

• Entry DOI: 10.2210/pdb5iii/pdb
• Related: 5IIJ 5IIK 5IIL 5IIM 5IIN 5IIO
• Descriptor: DNA polymerase lambda, DNA (5'-D(P*GP*CP*CP*G)-3'), DNA (5'-D(*CP*AP*GP*TP*AP*(DOC))-3'), ... (8 entities in total)
• Functional Keywords: transferase-dna complex, transferase/dna
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : Q9UGP5
• Total number of polymer chains: 4
• Total formula weight: 44285.27

Authors

Burak, M.J.,Guja, K.E.,Garcia-Diaz, M. (deposition date: 2016-03-01, release date: 2016-08-17, Last modification date: 2024-03-06)

Primary citation

Burak, M.J.,Guja, K.E.,Hambardjieva, E.,Derkunt, B.,Garcia-Diaz, M.
A fidelity mechanism in DNA polymerase lambda promotes error-free bypass of 8-oxo-dG.
Embo J., 35:2045-2059, 2016

PubMed 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.

PubMed: 27481934
DOI: 10.15252/embj.201694332

Experimental method

X-RAY DIFFRACTION (1.8 Å)