Title:Redox Regulation in the Base Excision Repair Pathway: Old and New Players as Cancer Therapeutic Targets
Volume: 27
Issue: 12
Author(s): Aleksandra Rajapakse, Amila Suraweera, Didier Boucher, Ali Naqi, Kenneth O'Byrne, Derek J. Richard and Laura V. Croft*
Affiliation:
- Queensland University of Technology, Faculty of Health, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Cancer and Ageing Research Program, Translational Research Institute, Brisbane, QLD,Australia
Keywords:
ROS, BER, APE1, hOGG1, hSSB1/NABP2/OBFC2B, DNA repair, cancer therapeutics.
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.
