Architecture of Y‐Family DNA Polymerases Relevant to Translesion DNA Synthesis as Revealed in Structural and Molecular Modeling Studies

Abstract

DNA adducts, which block replicative DNA polymerases (DNAPs), are often bypassed by lesion-bypass DNAPs, which are mostly in the Y-Family. Y-Family DNAPs can do non-mutagenic or mutagenic dNTP insertion, and understanding this difference is important, because mutations transform normal into tumorigenic cells. Y-Family DNAP architecture that dictates mechanism, as revealed in structural and modeling studies, is considered. Steps from adduct blockage of replicative DNAPs, to bypass by a lesion-bypass DNAP, to resumption of synthesis by a replicative DNAP are described. Catalytic steps and protein conformational changes are considered. One adduct is analyzed in greater detail: the major benzo[a]pyrene adduct (B[a]P-N2-dG), which is bypassed non-mutagenically (dCTP insertion) by Y-family DNAPs in the IV/κ-class and mutagenically (dATP insertion) by V/η-class Y-Family DNAPs. Important architectural differences between IV/κ-class versus V/η-class DNAPs are discussed, including insights gained by analyzing ~400 sequences each for bacterial DNAPs IV and V, along with sequences from eukaryotic DNAPs kappa, eta and iota. The little finger domains of Y-Family DNAPs do not show sequence conservation; however, their structures are remarkably similar due to the presence of a core of hydrophobic amino acids, whose exact identity is less important than the hydrophobic amino acid spacing.