Review article
Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1)

https://doi.org/10.1016/j.bmc.2017.01.028Get rights and content

Abstract

Human apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein which is essential in the base excision repair (BER) pathway of DNA lesions caused by oxidation and alkylation. This protein hydrolyzes DNA adjacent to the 5′-end of an apurinic/apyrimidinic (AP) site to produce a nick with a 3′-hydroxyl group and a 5′-deoxyribose phosphate moiety or activates the DNA-binding activity of certain transcription factors through its redox function. Studies have indicated a role for APE1/Ref-1 in the pathogenesis of cancer and in resistance to DNA-interactive drugs. Thus, this protein has potential as a target in cancer treatment. As a result, major efforts have been directed to identify small molecule inhibitors against APE1/Ref-1 activities. These agents have the potential to become anticancer drugs. The aim of this review is to present recent progress in studies of all published small molecule APE1/Ref-1 inhibitors. The structures and activities of APE1/Ref-1 inhibitors, that target both DNA repair and redox activities, are presented and discussed. To date, there is an urgent need for further development of the design and synthesis of APE1/Ref-1 inhibitors due to high importance of this protein target.

Introduction

DNA continuously undergoes changes. The loss of its purine bases, and thus, a loss of potentially vital genetic information is among these changes. A location in DNA without a base (apurinic/apyrimidinic or abasic sites) generates spontaneously, through damage-induced hydrolysis of base residue, or due to enzyme-catalyzed removal of alkylated or oxidized bases during base excision repair (BER).1 BER is the major pathway to repair DNA damage and to avert the mutagenic and cytotoxic effects arising from spontaneous oxidation, non-enzymatic alkylation and hydrolytic processes. BER recognizes and repairs modifications of bases, such as 5-hydroxyuracil, 8-oxoguanine and 3-methyladenine, as well as apurinic/apyrimidinic (AP) sites and DNA single strand breaks.2 At least 30 different proteins coordinate and process BER as a sequential molecular mechanism.3 Depending on the number of nucleotides incorporated during repair synthesis, BER is sub-divided into two major pathways: short patch involving replacement of a single nucleotide and long patch involving synthesis of 2–13 nucleotides and strand-displacement polymerization.4

The repair of AP sites performed by the BER system includes DNA cleavage according to three different mechanisms: hydrolysis catalyzed by AP endonuclease 1/redox effector factor 1 (APE1/Ref-1), and β- or β,δ-elimination performed by DNA glycosylases.5, 6 The major contribution to AP site cleavage in mammalian cells is provided by APE1/Ref-1 (∼95% of damages in the BER pathway). This protein as a reduction-oxidation (redox) factor interacts with transcription factors and maintains them in an active reduced state. Both functions have potential in cancer cell sensitization to chemotherapy.7

This review summarizes the various functions and activities of APE1/Ref-1 and the current picture of the development of the identified endonuclease and redox inhibitors. The structures, mechanism of action and therapeutic rationale of all potent APE1/Ref-1 inhibitors which reported to date are first described.

Section snippets

APE1/Ref-1

There are four potential incision sites for AP endonucleases, and these enzymes were classified in accordance with their incision sites: class I and II enzymes cleave 3′ and 5′, respectively, to the AP site, both generating 3′-OH and 5′-phosphate termini; class III and IV AP endonucleases cleave 3′ and 5′, respectively, to the AP site, producing 3′-phosphate and 5′-OH termini.8 Glycosylase-AP endonucleases are all known class I AP endonucleases, class II AP endonucleases include most AP

DNA repair and redox activities of APE1/Ref-1

The APE1/Ref-1’s C-terminal domain is responsible for the DNA repair activity.16 Short patch and long patch pathways are two branches of mammalian BER. These branches differ in the proteins involved and in the length of newly synthesized DNA fragment. A choice between them is still not clear, however the damage type and the glycosylase removing the lesion are involved. Short patch is the predominant BER pathway and repairs an alkylated or oxidized base starting with a DNA glycosylase which

APE1/Ref-1 in cancer and other diseases

APE1/Ref-1 plays a vital role in mammalian cells. Its implication in human pathologies is not unexpected.16 DNA damage and chronic oxidative stress were involved in various neurodegenerative disorders, including Alzheimer’s, Parkinson’s, Huntington’s diseases, and amyotrophic lateral sclerosis.45 Thus, deregulated cyclin-dependent kinase 5 performs a critical role in neuronal death. It was demonstrated that cyclin-dependent kinase 5 complexes phosphorylated APE1/Ref-1 at Thr232 and thus

APE1/Ref-1 inhibitors

As endonuclease activity of the C-terminus and redox activity of the N-terminus of APE1/Ref-1 are independent, thus, various compounds were reported as inhibitors for their active sites.12 The majority inhibitors of endonuclease activity are identified as specific for APE1/Ref-1, in that these agents do not interact with DNA and have no effect on Escherichia coli endonuclease IV. Methoxyamine, a nonspecific indirect inhibitor of this protein, binds irreversibly to AP sites in DNA and prevents

Conclusion

APE1/Ref-1 is a multifunctional protein that has an extended spectrum of activities. Disruptions in APE1/Ref-1 functions can be associated with various human pathologies such as cancer and cardiovascular and neurodegenerative diseases, which is due to the multitude of functions of this enzyme.146 This fact makes this enzyme a potential therapeutic target. It is also evident that APE1/Ref-1 repair activity correlates with anticancer agent resistance. Major efforts have been directed to design,

Acknowledgments

This work was supported by grant of Russian Scientific Foundation 16-13-10074 and by Program of RAS on Molecular and Cellular Biology. We thank Dr. Nadejda Dyrkheeva for reading this manuscript.

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      APE1 involves the DNA base excision repair (BER) pathway of all DNA damage including single-strand breaks, alkylation, oxidation, and abasic sites, and its activity accounts for about 95% of the total activity of all AP endonuclease in human cells [4,5]. APE1 also has co-transcriptional activity, which controls the intracellular redox state by inhibiting the production of reactive oxygen species (ROS), and regulating the activity of transcription factors associated with cancer occurrence and development, such as AP-1, p53, Egr-1, HLF, etc [6–10]. The abnormal expression of APE1 protein can induce various cancers.

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    This review is primarily intended for chemists, but we hope it can be useful for professionals in the medical field.

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