Redox Regulation in the Base Excision Repair Pathway: Old and New Players as Cancer Therapeutic Targets

Abstract

Background: Reactive Oxygen Species (ROS) are by-products of normal cellular metabolic processes, such as mitochondrial oxidative phosphorylation. While low levels of ROS are important signalling molecules, high levels of ROS can damage proteins, lipids and DNA. Indeed, oxidative DNA damage is the most frequent type of damage in the mammalian genome and is linked to human pathologies such as cancer and neurodegenerative disorders. Although oxidative DNA damage is cleared predominantly through the Base Excision Repair (BER) pathway, recent evidence suggests that additional pathways such as Nucleotide Excision Repair (NER) and Mismatch Repair (MMR) can also participate in clearance of these lesions. One of the most common forms of oxidative DNA damage is the base damage 8-oxoguanine (8-oxoG), which if left unrepaired may result in G:C to A:T transversions during replication, a common mutagenic feature that can lead to cellular transformation. Objective: Repair of oxidative DNA damage, including 8-oxoG base damage, involves the functional interplay between a number of proteins in a series of enzymatic reactions. This review describes the role and the redox regulation of key proteins involved in the initial stages of BER of 8-oxoG damage, namely Apurinic/Apyrimidinic Endonuclease 1 (APE1), human 8-oxoguanine DNA glycosylase-1 (hOGG1) and human single-stranded DNA binding protein 1 (hSSB1). Moreover, the therapeutic potential and modalities of targeting these key proteins in cancer are discussed. Conclusion: It is becoming increasingly apparent that some DNA repair proteins function in multiple repair pathways. Inhibiting these factors would provide attractive strategies for the development of more effective cancer therapies.

Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review

“…A multiplicity of DNA repair systems has evolved in order to counteract these lesions. Some of these repair mechanisms involve base excision repair (BER), mismatch repair (MMR), post-replication repair and error-prone repair systems ( Iyama and Wilson, 2013 ; Vaz et al, 2017 ; Rajapakse et al, 2019 ). BER features three steps: excision of the damaged base; use of the undamaged DNA strand as a template to fill in the gap via DNA polymerase; and DNA ligase to seal the process ( Sancar, 1994 ).…”

Biomarkers of tumor invasiveness in proteomics (Review)

“…Thus, novel treatment strategies aimed at its downregulation have been proposed to increase the accumulation of ROS, decrease key glycolytic enzymes and finally, enhance the radiosensitivity of lung cancer cells (283). The role of this protein in the regulation of the base excision repair pathway (284) and in the protection against DNA damage events (285) has recently been investigated.…”

Shedding a New Light on Skin Aging, Iron- and Redox-Homeostasis and Emerging Natural Antioxidants

“…Due to its dual effect as ROS generator and LI enhancer, UVA is referred to as the main oxidising component of sunlight [70,71]. Recent studies have highlighted that UVA can compromise DNA repair in human cells, and it does this by damaging DNA repair proteins, some of which are redox-regulated [72,73]. In addition, UVA radiation is capable of inducing both direct and indirect damage to DNA, as well as inhibiting DNA repair mechanisms leading to the initiation of skin carcinogenesis.…”