Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

Abstract

Base excision repair (BER) is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen damaged (oxidized or alkylated) or inappropriate bases that are generated endogenously or induced by genotoxicants, predominantly, reactive oxygen species (ROS). BER involves 4-5 steps starting with base excision by a DNA glycosylase, followed by a common pathway usually involving an AP-endonuclease (APE) to generate 3′ OH terminus at the damage site, followed by repair synthesis with a DNA polymerase and nick sealing by a DNA ligase. This pathway is also responsible for repairing DNA single-strand breaks with blocked termini directly generated by ROS. Nearly all glycosylases, far fewer than their substrate lesions particularly for oxidized bases, have broad and overlapping substrate range, and could serve as back-up enzymes in vivo. In contrast, mammalian cells encode only one APE, APE1, unlike two APEs in lower organisms. In spite of overall similarity, BER with distinct subpathways in the mammals is more complex than in E. coli. The glycosylases form complexes with downstream proteins to carry out efficient repair via distinct subpathways one of which, responsible for repair of strand breaks with 3′ phosphate termini generated by the NEIL family glycosylases or by ROS, requires the phosphatase activity of polynucleotide kinase instead of APE1. Different complexes may utilize distinct DNA polymerases and ligases. Mammalian glycosylases have nonconserved extensions at one of the termini, dispensable for enzymatic activity but needed for interaction with other BER and non-BER proteins for complex formation and organelle targeting. The mammalian enzymes are sometimes covalently modified which may affect activity and complex formation. The focus of this review is on the early steps in mammalian BER for oxidized damage.

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

“…However, recent studies have revealed that BER is much more complex, involving a network of distinct and integrated cell cycle-and genome-specific sub-pathways in which numerous noncanonical proteins take part (58,59). Notably, many of these proteins are involved in RNA-metabolism processes.…”

A randomized, double-blind, placebo-controlled, clinical trial on probiotic soy milk and soy milk: effects on epigenetics and oxidative stress in patients with type II diabetes

“…ROS has an intracellular signaling effect in healthy cells, but an enhancement of ROS production or lack of antioxidant production results in oxidative stress and may cause DNA double-strand break (Waris and Ahsan 2006). ROS can cause transition mutation in DNA because it induces deamination of cytosine to uracil or 5-hydroxyuracil, and during DNA replication, uracil and 5-hydroxyuracil pair with adenosine, resulting in G:C to A:T transition mutation (Hegde et al 2008).…”

Neil3 and NEIL1 DNA Glycosylases Remove Oxidative Damages from Quadruplex DNA and Exhibit Preferences for Lesions in the Telomeric Sequence Context

“…DNA glycosylases are the first enzymes in base excision repair that recognize damaged bases, excise the lesions, and provide substrates for later enzymes in the pathway (9). Five DNA glycosylases that are specific for oxidative DNA base damages have been identified in human cells, namely OGG1, NTH1, NEIL1, NEIL2, and NEIL3 (2,3).…”