Abstract
Genomic fidelity in the humans is continuously challenged by genotoxic reactive oxygen species (ROS) generated both endogenously during metabolic processes, and by exogenous agents. Mispairing of most ROS-induced oxidized base lesions during DNA replication induces mutations. Although bulky base adducts induced by ultraviolet light and other environmental mutagens block replicative DNA polymerases, most oxidized base lesions do not block DNA synthesis. In 8-oxo-G:A mispairs generated by the incorporation of A opposite unrepaired 8-oxo-G, A is removed by MutYH (MYH) for post-replicative repair, and other oxidized base lesions must be repaired prior to replication in order to prevent mutation fixation. Our earlier studies documented S phase-specific overexpression of endonuclease VIII-like 1 (NEIL1) DNA glycosylase (DG), one of five oxidized base excision repair (BER)-initiating enzymes in mammalian cells, and its high affinity for replication fork-mimicking single-stranded (ss)DNA substrates. We recently provided experimental evidence for the role of NEIL1 in replicating-strand repair, and proposed the “cowcatcher” model of pre-replicative BER, where NEIL1’s nonproductive binding to the lesion base in ssDNA template blocks DNA chain elongation, causing fork regression. Repair of the lesion in the then re-annealed duplex is carried out by NEIL1 in association with the DNA replication proteins. In this commentary, we highlight the critical role of pre-replicative BER in preventing mutagenesis, and discuss the distinction between pre-replicative vs. post-replicative BER.
Highlights
Reactive oxygen species (ROS) generated as by-products of cellular respiration in aerobic organisms and by exogenous genotoxic agents are a major threat to the genome, which is vulnerable to oxidative damage
Replication after unwinding of the duplex genome is vulnerable to oxidation by ROS, which induces a plethora of oxidized DNA base lesions and oxidized sugar fragments, as well as DNA
We have shown NEIL1’s interaction with long patch (LP-)base excision repair (BER)–specific DNA
Summary
Reactive oxygen species (ROS) generated as by-products of cellular respiration in aerobic organisms and by exogenous genotoxic agents are a major threat to the genome, which is vulnerable to oxidative damage. Repair of most mutagenic base lesions except 8-oxoG (e.g., 5-hydroxyuracil (5-OHU), thymine glycol (TG), hydroxycytosine (5-OHC), formamidopyrimidines (FapyA), 7,8-dihydro-8-oxoadenine (8-oxo-A), uracil glycol) must be carried out prior to replication in order to prevent mutation fixation How such lesions, that do not block replicative polymerase δ (Polδ), are flagged for pre-replicative repair without causing double-strand breaks (DSBs) was unclear. Our recent study showed that endonuclease VIII-like 1 (NEIL1) DNA glycosylase (DG), a unique base-excision repair (BER)-initiating enzyme in mammalian cells binds to lesion sites in ssDNA substrates in vitro to facilitate fork regression and pre-replicative repair of the damaged base in the re-annealed duplex DNA [3]. Model of pre-replicative DNA repair of oxidized bases that is critical to maintenance of genome fidelity
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