8vfa

Publication Abstract from PubMed

N6-(2-deoxy-alpha,beta-d-erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamido-pyrimidine (Fapy*dG) is formed from a common intermediate and in comparable amounts to the well-studied mutagenic DNA lesion 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodGuo). Fapy*dG preferentially gives rise to G --> T transversions and G --> A transitions. However, the molecular basis by which Fapy*dG is processed by DNA polymerases during this mutagenic process remains poorly understood. To address this we investigated how DNA polymerase beta (Pol beta), a model mammalian polymerase, bypasses a templating Fapy*dG, inserts Fapy*dGTP, and extends from Fapy*dG at the primer terminus. When Fapy*dG is present in the template, Pol beta incorporates TMP less efficiently than either dCMP or dAMP. Kinetic analysis revealed that Fapy*dGTP is a poor substrate but is incorporated approximately 3-times more efficiently opposite dA than dC. Extension from Fapy*dG at the 3'-terminus of a nascent primer is inefficient due to the primer terminus being poorly positioned for catalysis. Together these data indicate that mutagenic bypass of Fapy*dG is likely to be the source of the mutagenic effects of the lesion and not Fapy*dGTP. These experiments increase our understanding of the promutagenic effects of Fapy*dG.

Biochemical and structural characterization of Fapy*dG replication by Human DNA polymerase beta.,Gao S, Oden PN, Ryan BJ, Yang H, Freudenthal BD, Greenberg MM Nucleic Acids Res. 2024 Apr 18:gkae277. doi: 10.1093/nar/gkae277. PMID:38634780^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.