Structural Basis for Error-Free Bypass of the 5-N-Methylformamidopyrimidine-dG Lesion by Human DNA Polymerase η and Sulfolobus solfataricus P2 Polymerase IV.

Patra A, Banerjee S, Johnson Salyard TL, Malik CK, Christov PP, Rizzo CJ, Stone MP, Egli M
J Am Chem Soc. 2015 137 (22): 7011-4

PMID: 25988947 · PMCID: PMC4545269 · DOI:10.1021/jacs.5b02701

N(6)-(2-Deoxy-D-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-N-methylformamidopyrimidine (MeFapy-dG) arises from N7-methylation of deoxyguanosine followed by imidazole ring opening. The lesion has been reported to persist in animal tissues. Previous in vitro replication bypass investigations of the MeFapy-dG adduct revealed predominant insertion of C opposite the lesion, dependent on the identity of the DNA polymerase (Pol) and the local sequence context. Here we report crystal structures of ternary Pol·DNA·dNTP complexes between MeFapy-dG-adducted DNA template:primer duplexes and the Y-family polymerases human Pol η and P2 Pol IV (Dpo4) from Sulfolobus solfataricus. The structures of the hPol η and Dpo4 complexes at the insertion and extension stages, respectively, are representative of error-free replication, with MeFapy-dG in the anti conformation and forming Watson-Crick pairs with dCTP or dC.

MeSH Terms (6)

Deoxyguanosine DNA-Directed DNA Polymerase DNA Damage Models, Molecular Pyrimidines Sulfolobus solfataricus

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