[Frontiers In Bioscience, Landmark, 22, 1493-1522, March 1, 2017]

Base excision repair of oxidative DNA damage: from mechanism to disease

Amy M. Whitaker1, Matthew A. Schaich1, Mallory R. Smith1, Tony S. Flynn1, Bret. D. Freudenthal1

1Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, 66160

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Oxidative DNA damage
2.2. Mammalian base excision repair (BER): an overview
3. Identification of oxidative DNA damage during BER
3.1. Classification of mammalian DNA glycosylases
3.2. Detection of damaged bases by DNA glycosylases
3.3. Excision strategies of DNA glycosylases
4. Processing of BER intermediates
4.1. Endo- and exo- nuclease activities of APE1
4.2. Lyase and polymerase activities of pol β
4.3. Ligation and final repair of DNA
5. Multi-protein co-complexes facilitate BER
5.1. Scaffolding proteins
5.2. Substrate channeling
6. Human disease and BER
6.1. Knockout models
6.2. Neurological disorders
6.3. Cancer
7. Perspective
8. Acknowledgements
9. References

1. ABSTRACT

Reactive oxygen species continuously assault the structure of DNA resulting in oxidation and fragmentation of the nucleobases. Both oxidative DNA damage itself and its repair mediate the progression of many prevalent human maladies. The major pathway tasked with removal of oxidative DNA damage, and hence maintaining genomic integrity, is base excision repair (BER). The aphorism that structure often dictates function has proven true, as numerous recent structural biology studies have aided in clarifying the molecular mechanisms used by key BER enzymes during the repair of damaged DNA. This review focuses on the mechanistic details of the individual BER enzymes and the association of these enzymes during the development and progression of human diseases, including cancer and neurological diseases. Expanding on these structural and biochemical studies to further clarify still elusive BER mechanisms, and focusing our efforts toward gaining an improved appreciation of how these enzymes form co-complexes to facilitate DNA repair is a crucial next step toward understanding how BER contributes to human maladies and how it can be manipulated to alter patient outcomes.

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Key Words: Base excision repair, Oxidative DNA damage, DNA repair, Review

Send correspondence to: Bret D. Freudenthal, 4015 WHW, Laboratory of Genome Maintenance and Structural Biology, Department of Biochemistry Molecular Biology, and Department of Cancer Biology, University of Kansas Medical Center Kansas, 66160, Tel: 913-588-5560, Fax: 913-588-7440, E-mail: bfreudenthal@kumc.edu