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

Publication Type:

Journal Article

Authors:

Patra, Amritraj; Banerjee, Surajit; Johnson Salyard, Tracy L; Malik, Chanchal K; Christov, Plamen P; Rizzo, Carmelo J; Stone, Michael P; Egli, Martin

Source:

J Am Chem Soc, Volume 137, Issue 22, p.7011-4 (2015)

Keywords:

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

Abstract:

<p>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.</p>