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.
Highlights
DNA damaging agents cause mutations that initiate tumor formation, which makes sense given that tumor cells have mutations in key growth control genes that lead to improperly regulated cell growth [1, 2]
Most translesion synthesis (TLS)-DNA polymerases (DNAPs) are in the Y-Family [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22], where humans have three templatedirected members, yeast has one, and E. coli has two
We focus on structural considerations that relate to lesion bypass, though we briefly describe each of the four subclasses of eukaryotic Y-Family DNAPs: REV1, DNAP κ, DNAP η, and DNAP ι
Summary
DNA damaging agents (genotoxins) cause mutations that initiate tumor formation, which makes sense given that tumor cells have mutations in key growth control genes that lead to improperly regulated cell growth [1, 2]. Oxidative metabolism forms reactive oxygen species that generate lipid peroxidation products that give exocyclic adducts, some of which can ring-open to N2-dG adducts in ds-DNA [78] and might be bypassed by DNAP IV, though this has not been investigated experimentally These observations have led several groups to speculate that the cellular rationale for the genesis of the IV/κ-class of Y-Family. UmuD2C (not UmuD’2C) is thought to slow down normal DNA replication in response to DNA damage, allowing additional time for lesion removal, which is considered a DNA damage checkpoint analogous to what happens in eukaryotic cells [79] Another mechanism to accomplish this was recently described: DNAP II or IV can associate with the DnaB helicase and slow down the replication fork [80]. DNAP IV is elevated in stationary phase (∼7500/cell) and is implicated in adaptive mutagenesis [82]
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