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Going APE over ref-1

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Abstract

The DNA base excision repair (BER) pathway is responsible for the repair of cellular alkylation and oxidative DNA damage. A crucial and the second step in the BER pathway involves the cleavage of baseless sites in DNA by an AP endonuclease. The major AP endonuclease in mammalian cells is Ape1/ref-1. Ape1/ref-1 is a multifunctional protein that is not only responsible for repair of AP sites, but also functions as a reduction-oxidation (redox) factor maintaining transcription factors in an active reduced state. Ape1/ref-1 has been shown to stimulate the DNA binding activity of numerous transcription factors that are involved in cancer promotion and progression such as Fos, Jun, NF(B, PAX, HIF-1(, HLF and p53. Ape1/ref-1 has also been implicated in the activation of bioreductive drugs which require reduction in order to be active and has been shown to interact with a subunit of the Ku antigen to act as a negative regulator of the parathyroid hormone promoter, as well as part of the HREBP transcription factor complex. Ape1/ref-1 levels have been found to be elevated in a number of cancers such as ovarian, cervical, prostate, rhabdomyosarcomas and germ cell tumors and correlated with the radiosensitivity of cervical cancers. In this review, we have attempted to try and assimilated as much data concerning Ape1/ref-1 and incorporate the rapidly growing information on Ape1/ref-1 in a wide variety of functions and systems.

Introduction

Apurinic/apyrimidinic endonuclease/redox effector factor (Ape1/Ref-1) is a protein with multifunctional roles in cells impacting on a wide variety of important cellular functions (Fig. 1). It acts on apurinic/apyrimidinic (AP) sites in DNA as a major member of the base excision repair (BER) pathway, is involved in oxidative DNA damage repair, and stimulates the DNA binding activity of AP-1 (Fos, Jun) proteins, as well as nuclear factor-κB (NF-κB), polyoma virus enhancer-binding protein 2 (PEBP2), early growth response-1 (Egr-1), Myb, members of the ATF/CREB family, HIF-1α (hypoxia inducible factor-1α), HLF (HIF-like factor), Pax-5, and Pax-8 [2], [25], [52], [53], [71], [149], [150], [156]. The DNA binding activity of these latter proteins is sensitive to reduction–oxidation (redox). Ape1/Ref-1, which is the major AP-1 redox activity in cells, represents a novel redox component of signal transduction processes that regulate eukaryotic gene expression. Recent developments also have implicated Ape1/Ref-1 as a major controlling factor for p53 activity through redox dependent and independent mechanisms [33], [60]. Ape1/Ref-1 has been shown to be closely linked to apoptosis [110] and altered levels or cellular location of Ape1/Ref-1 have been found in some cancers, including ovarian, cervical, prostate and germ cell tumors [66], [67], [88], [153]. Therefore, Ape1/Ref-1 appears to form a unique link between the DNA BER pathway, cancer, transcription factor regulation, oxidative signaling, and cell-cycle control.

Section snippets

AP site formation and base excision repair

AP sites are a common type of DNA lesion [28], [90]. In fact, the in vitro spontaneous depurination rate is estimated at ∼10,000 bases per cell per day [73], [91]. Nakamura and Swenberg recently expanded these findings in vivo using a slot blot assay, and estimate 2000–8000 sites form per cell per day depending on the tissue type [90]. The maximum number of AP sites is found in the brain, followed by heart and colon, whereas liver, lung, and kidney have the lowest rates in rats. Interestingly,

Ape1/Ref-1 genes, proteins, and structure

AP endonucleases are classified into two families according to their homology to E. coli endonucleases: exonuclease III (xth) and endonuclease IV (nfo). The first family of AP endonucleases derives from organisms across several phyla including, exonulcease III (E. coli), Exo A (Steptococcus pneumoniae), Rrp 1 (Drosophila melanogaster), Arp (Arabidopsis thaliana), Apn2 (S. cerevisiae), APEX (mouse), BAP1 (bovine), rAPE (rat), chAPE1 (hamster), and Ape1/Ref-1 (humans; previously referred to as

Ape1/Ref-1 tissue and cellular location

Since Ape1/Ref-1 is an important protein for cellular survivability, it was expected to be ubiquitously expressed in cells. Indeed, Ape1/Ref-1 expression is ubiquitous, however, it exhibits a complex and heterogeneous staining pattern that differs among tissue types and even differs between neighboring cells. At least five different patterns of Ape1/Ref-1 staining are observed; presumably, the expression complexity is congruent with its multifunctional roles. First, regional variation in the

Regulation of gene expression

Ape1/Ref-1 is regulated at both the transcriptional and post-translational level. In terms of transcriptional regulation, the effects of reactive oxygen species (ROS) on Ape1/Ref-1 induction have been the most intensely studied (Table 1). In both in vivo and in vitro studies, oxidative agents induce Ape1/Ref-1 [35], [39], [40], [107], [131], [133], [137], [156] (although see [23]). Induction is characterized by a transient increase in Ape1/Ref-1 protein and mRNA. The exception to this is a

Regulation of transcription factors

The importance of reduction–oxidation (redox) control of transcription factors was suggested when v-Jun, a transcription factor with transforming and oncogenic qualities, was shown to have a serine mutation at the normally conserved cysteine residue [93]. Moreover, when a cysteine to serine mutation was introduced in Fos, it resulted in an increase in DNA binding, a resistance to oxidizing agents and an increase in cellular transforming activity (i.e. colony formation) [1], [95]. Thus, the

Over-expression of Ape1/Ref-1 and antisense studies

Ape1/Ref-1 is a critical component of BER. Indeed, unrepaired abasic sites can result in a block to DNA replication, cytotoxicity, mutations, and genetic instability [74]. The functional importance of this protein is underscored by the findings that mice nullizygous for Ape1/Ref-1 gene are embryonic lethal [152]. Consequently, a number of studies have investigated the effects of manipulating cellular levels of Ape1/Ref-1 with the expectation that healthy normal cells could be afforded added

Concluding remarks

Ape1/Ref-1 is a multifunctional protein that is critical to the survival of animals and, presumably, humans [152]. It impacts on a wide variety of important cellular functions. As a major member of the BER pathway, Ape1/Ref-1 acts on AP sites in DNA, which, if left unrepaired, can result in a block to DNA replication, cytotoxicity, mutations, and genetic instability [74]. Ape1/Ref-1 has also been found to stimulate the transcriptional activity of numerous transcription factors that have

Acknowledgements

We would like to thank David M. Wilson III (Lawrence Livermore National Laboratory) and Martin L. Smith (Indiana University Medical School) for their reading and comments on this manuscript pre-submission. We also want to thank Dr. Daniel Barsky, Lawrence Livermore National Laboratory, for generating and giving us the Ape1/Ref-1 structure found in Fig. 5. The authors were supported in this endeavor by NIH/NCI Program Project Grant PO1-CA75426 and by NIH Grants CA76643, ES07815, NS38506, the

References (158)

  • T.M. Gottlieb et al.

    p53 in growth control and neoplasia

    Biochim. Biophys. Acta

    (1996)
  • S. Grosch et al.

    Transcriptional activation of apurinic/apyrimidinic endonuclease (Ape, Ref-1) by oxidative stress requires CREB

    Biochem. Biophys. Res. Commun.

    (1999)
  • M.W. Halterman et al.

    HIF-1α and p53 promote hypoxia-induced delayed neuronal death in models of CNS ischemia

    Exp. Neurol.

    (1999)
  • W.K. Hansen et al.

    Creation of a fully functional human chimeric DNA repair protein. Combining O6-methylguanine DNA methyltransferase (MGMT) and AP endonuclease (APE/redox effector factor 1 (Ref-1)) DNA repair proteins

    J. Biol. Chem.

    (1998)
  • L. Harrison et al.

    Comparison of the promoters of the mouse (APEX) and human (APE) apurinic endonuclease genes

    Mutat. Res.

    (1997)
  • L. Harrison et al.

    Characterization of the promoter region of the human apurinic endonuclease gene (APE)

    J. Biol. Chem.

    (1995)
  • L.E. Huang et al.

    Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its α subunit

    J. Biol. Chem.

    (1996)
  • T. Izumi et al.

    Intragenic suppression of an active site mutation in the human apurinic/apyrimidinic endonuclease

    J. Mol. Biol.

    (1999)
  • J. Kim et al.

    Implication of mammalian ribosomal protein S3 in the processing of DNA damage

    J. Biol. Chem.

    (1995)
  • D. Lando et al.

    A redox mechanism controls differential DNA binding activities of hypoxia-inducible factor (HIF) 1α and the HIF-like factor

    J. Biol. Chem.

    (2000)
  • A.J. Levine

    p53 the cellular gatekeeper for growth and division

    Cell

    (1997)
  • A. Mansouri et al.

    Pax genes and their roles in cell differentiation and development

    Curr. Opinion Cell. Biol.

    (1996)
  • Y. Masuda et al.

    Dynamics of the interaction of human apurinic endonuclease (Ape1) with its substrate and product

    J. Biol. Chem.

    (1998)
  • Y. Masuda et al.

    Rapid dissociation of human apurinic endonuclease (Ape1) from incised DNA induced by magnesium

    J. Biol. Chem.

    (1998)
  • H. Masutani et al.

    Transactivation of an inducible anti-oxidative stress protein, human thioredoxin by HTLV-I Tax

    Immunol. Lett.

    (1996)
  • S. Mitra et al.

    Complexities of DNA base excision repair in mammalian cells

    Mol. Cells

    (1997)
  • S. Mitra et al.

    Regulation of repair of alkylation damage in mammalian genomes

    Prog. Nucleic Acid Res. Mol. Biol.

    (1993)
  • Y. Morita-Fujimura et al.

    Early decrease in apurinic/apyrimidinic endonuclease is followed by DNA fragmentation after cold injury-induced brain trauma in mice

    Neuroscience

    (1999)
  • H. Nakshatri et al.

    Subunit association and DNA binding activity of the heterotrimeric transcription factor NF-Y is regulated by cellular redox

    J. Biol. Chem.

    (1996)
  • T. Okazaki et al.

    A redox factor protein, Ref-1, is involved in negative gene regulation by extracellular calcium

    J. Biol. Chem.

    (1994)
  • Y. Ono et al.

    Stable expression in rat glioma cells of sense and antisense nucleic acids to a human multifunctional DNA repair enzyme APEX nuclease

    Mutat. Res.

    (1994)
  • Y. Ono et al.

    Developmental expression of APEX nuclease, a multifunctional DNA repair enzyme, in mouse brains

    Brain Res. Dev. Brain Res.

    (1995)
  • C. Abate et al.

    Redox regulation of Fos and Jun DNA-binding activity in vitro

    Science

    (1990)
  • E. Babiychuk et al.

    The Arabidopsis thaliana apurinic endonuclease Arp reduces human transcription factors Fos and Jun

    Proc. Natl. Acad. Sci. U. S. A.

    (1994)
  • G. Barzilay et al.

    Structure and function of apurinic/apyrimidinic endonucleases

    Bioessays

    (1995)
  • G. Barzilay et al.

    Identification of critical active-site residues in the multifunctional human DNA repair enzyme HAP1

    Nat. Struct. Biol.

    (1995)
  • G. Barzilay et al.

    Site-directed mutagenesis of the human DNA repair enzyme HAP1: identification of residues important for AP endonuclease and RNase H activity

    Nucleic Acids Res.

    (1995)
  • R.A. Bennett et al.

    Interaction of human apurinic endonuclease and DNA polymerase β in the base excision repair pathway

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • P.D. Boucher et al.

    Partial characterization of the human CYP1A1 negatively acting transcription factor and mutational analysis of its cognate DNA recognition sequence

    Mol. Cell. Biol.

    (1995)
  • P. Carrero et al.

    Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1α

    Mol. Cell. Biol.

    (2000)
  • M.A. Chaudhry et al.

    Induction of double-strand breaks by S1 nuclease, mung bean nuclease and nuclease P1 in DNA containing abasic sites and nicks

    Nucleic Acids Res.

    (1995)
  • D.S. Chen et al.

    Two distinct human DNA diesterases that hydrolyze 3′-blocking deoxyribose fragments from oxidized DNA

    Nucleic Acids Res.

    (1991)
  • D.S. Chen et al.

    Reduction of radiation cytotoxicity by human apurinic endonuclease in a radiation-sensitive Escherichia coli mutant

    Radiat. Res.

    (1993)
  • D.S. Chen et al.

    Biological responses of human apurinic endonuclease to radiation-induced DNA damage

    Ann. NY Acad. Sci.

    (1994)
  • B. Christy et al.

    DNA binding site of the growth factor-inducible protein Zif268

    Proc. Natl. Acad. Sci. U. S. A.

    (1989)
  • B. Demple et al.

    Repair of oxidative damage to DNA: enzymology and biology

    Annu. Rev. Biochem.

    (1994)
  • B. Demple et al.

    Cloning and expression of APE, the cDNA encoding the major human apurinic endonuclease: definition of a family of DNA repair enzymes

    Proc. Natl. Acad. Sci. U. S. A.

    (1991)
  • J.R. Duguid et al.

    Differential cellular and subcellular expression of the human multifunctional apurinic/apyrimidinic endonuclease (APE/Ref-1) DNA repair enzyme

    Cancer Res.

    (1995)
  • M. Edwards et al.

    APE/Ref-1 responses to ischemia in rat brain

    Neuroreport

    (1998)
  • M. Edwards et al.

    APE/Ref-1 responses to oxidative stress in aged rats

    J. Neurosci. Res.

    (1998)
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