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

[ Vol. 27 , Issue. 12 ]

Author(s):

Aleksandra Rajapakse, Amila Suraweera, Didier Boucher, Ali Naqi, Kenneth O'Byrne, Derek J. Richard and Laura V. Croft*   Pages 1901 - 1921 ( 21 )

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.

Keywords:

ROS, BER, APE1, hOGG1, hSSB1/NABP2/OBFC2B, DNA repair, cancer therapeutics.

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, 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, 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, Department of Chemistry, Pennsylvania State University, 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, 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, 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



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