The multifunctional DNA repair/redox enzyme Ape1/Ref-1 promotes survival of neurons after oxidative stress

Vasko, Michael R.; Guo, Caixia; Kelley, Mark R.

doi:10.1016/j.dnarep.2004.11.006

Cited by 117 publications

(143 citation statements)

References 45 publications

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“…IC 50 concentrations of cisplatin were 9.09-(A2780) or 4.63-fold (CP70) lower than those for cisplatin (MTT assay). Our results are supported by those of others in that the suppression of APE1 results in hypersensitivity to chemotherapeutic agents (10,26,27). Additionally, targeted reduction of Ape1/Ref-1 protein by specific anti-sense oligonucleotides renders mammalian cells hypersensitive to methylmethane sulfonate (MMS), H 2 O 2 , bleomycin, temozolomide (TMZ) and gemcitabine (22,28,29).…”

Section: Cell Cycle Perturbations Aftersupporting

confidence: 88%

Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor

Zhang

Wang²,

Xiang³

et al. 2009

Int J Oncol

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Abstract.Resistance to platinum is a major limitation for the treatment of ovarian cancer. In an effort to overcome the platinum resistance problem in ovarian cancer treatment, we explored the correlation between cisplatin resistance and the human AP endonuclease (APE1 or Ref-1). APE1/Ref-1 is a multifunctional protein that is not only an essential enzyme in base excision repair pathway, but also acts as a major redox-signaling factor that has a wide variety of important cellular functions including transcription factor regulation, oxidative signaling and cell cycle control. In this study, we

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Section: Cell Cycle Perturbations Aftersupporting

confidence: 88%

Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor

Zhang

Wang²,

Xiang³

et al. 2009

Int J Oncol

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“…DNA repair activity, in particular activation of APE1, represents an interesting point of control for cell death. Long understood to lead to genetic mutations associated with spontaneous tumor formation, AP sites have also been found to induce cell death in yeast (5), and deficiency in APE1 expression and activity exacerbates oxidative injury in multiple models, including neurons (12,20,21). Unrepaired AP sites accumulate following cerebral ischemia (4,6), and sustained decrease in APE1 protein expression has been observed to precede cell death in injured cell populations (10,22,23) (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, APE1 activity is enhanced by sublethal insults (6). APE1 expression and activity are associated with several neuroprotective paradigms, including ischemic preconditioning and overexpression of copper/ zinc superoxide dismutase (4,11), and overexpression of APE1 protects against oxidative cell death in cultured neurons (12). However, a direct contribution of APE1 to brain neuroprotection has yet to be established.…”

mentioning

confidence: 99%

Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia

Stetler

Gao

Zukin

et al. 2010

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

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Inducible DNA repair via the base-excision repair pathway is an important prosurvival mechanism activated in response to oxidative DNA damage. Elevated levels of the essential base-excision repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 correlate closely with neuronal survival against ischemic insults, depending on the CNS region, protective treatments, and degree of insult. However, the precise mechanisms by which this multifunctional protein affords protection and is activated by upstream signaling pathways in postischemic neurons are not well delineated. Here we show that intracerebral administration of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenously occurring small neuropeptide, induces expression of APE1 in hippocampal neurons. Induction of APE1 expression requires PKAand p38-dependent phosphorylation of cAMP response-element binding and activating transcription factor 2, which leads to transactivation of the APE1 promoter. We further show that PACAP markedly reduces oxidative DNA stress and hippocampal CA1 neuronal death following transient global ischemia. These effects occurred,atleastinpart,viaenhancedAPE1expression.Furthermore, the DNA repair function of APE1 was required for PACAP-mediated neuroprotection. Thus, induction of DNA repair enzymes may be a uniquestrategy forneuroprotectionagainsthippocampalinjury.activating transcription factor 2 | cAMP response-element binding | delayed neurodegeneration | DNA repair | oxidative stress O xidative stress is a hallmark of neurological disorders, including cerebral ischemia. Ischemic injury rapidly elicits oxidative DNA damage either directly via reactive oxygen species attack or indirectly via oxidization of lipids or proteins (1-3). These actions induce DNA lesions, involving base modifications and damage to the sugar moiety in the DNA, formation of abasic (apurinic/apyrimidinic, AP) sites, single strand breaks, and DNA intra-or interstrand crosslinks. Of these lesions, AP sites and single strand breaks are highly prevalent types of DNA damage in insulted neurons (4). Whereas the accumulation of unrepaired DNA ultimately induces cell death, active repair of DNA promotes cell survival (4-6).In neurons, base-excision repair (BER) is the predominant mechanism for repair of oxidative DNA lesions (7). BER is a three-step process. First, 5′-acting AP endonuclease 1 (APE1, also known as redox-effector factor 1) cleaves the phosphodiester backbone, then β-polymerase or alternative repair proteins, such as FEN1 or PCNA, fill in the gap with newly synthesized nucleotides, and finally a DNA ligase seals the nick. In several models of ischemia, oxidative DNA damage is reversible in regions that survive (4,6,8), raising the possibility that repair of DNA damage via BER is required for cell survival following ischemia.APE1 is an attractive target for neuroprotection, as it is a critical component of the BER process (9) and as also has redox and transcription-regulation activities. Following cerebral ischemi...

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“…APE1 is, in general, highly expressed in the CNS, with some variability among the different cell types and regions of the human brain, including the existence of distinct nuclear and cytoplasmic distribution patterns [reviewed in Wilson and McNeill (229)]. Early investigations demonstrated that APE1 depletion by siRNA in primary rat hippocampal or sensory neuronal cell cultures results in reduced cell viability, as well as increased apoptosis and DNA damage, after hydrogen peroxide treatment (216). Jiang et al found that inhibition of AP site repair using the inhibitor, methoxyamine, and not inhibition of the redox activity of APE1, induced hypersensitivity of differentiated (post-mitotic) SH-SY5Y neural cells to a range of oxidizing agents (92).…”

Section: Neuropathologymentioning

confidence: 99%

Human Apurinic/Apyrimidinic Endonuclease 1

2014

Antioxidants & Redox Signaling

228

221

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Significance: Human apurinic/apyrimidinic endonuclease 1 (APE1, also known as REF-1) was isolated based on its ability to cleave at AP sites in DNA or activate the DNA binding activity of certain transcription factors. We review herein topics related to this multi-functional DNA repair and stress-response protein. Recent Advances: APE1 displays homology to Escherichia coli exonuclease III and is a member of the divalent metal-dependent a/b fold-containing phosphoesterase superfamily of enzymes. APE1 has acquired distinct active site and loop elements that dictate substrate selectivity, and a unique N-terminus which at minimum imparts nuclear targeting and interaction specificity. Additional activities ascribed to APE1 include 3¢-5¢ exonuclease, 3¢-repair diesterase, nucleotide incision repair, damaged or site-specific RNA cleavage, and multiple transcription regulatory roles. Critical Issues: APE1 is essential for mouse embryogenesis and contributes to cell viability in a genetic background-dependent manner. Haploinsufficient APE1 +/ -mice exhibit reduced survival, increased cancer formation, and cellular/tissue hyper-sensitivity to oxidative stress, supporting the notion that impaired APE1 function associates with disease susceptibility. Although abnormal APE1 expression/localization has been seen in cancer and neuropathologies, and impaired-function variants have been described, a causal link between an APE1 defect and human disease remains elusive. Future Directions: Ongoing efforts aim at delineating the biological role(s) of the different APE1 activities, as well as the regulatory mechanisms for its intra-cellular distribution and participation in diverse molecular pathways. The determination of whether APE1 defects contribute to human disease, particularly pathologies that involve oxidative stress, and whether APE1 small-molecule regulators have clinical utility, is central to future investigations. Antioxid. Redox Signal. 20,

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The multifunctional DNA repair/redox enzyme Ape1/Ref-1 promotes survival of neurons after oxidative stress

Cited by 117 publications

References 45 publications

Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor

Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor

Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia

Human Apurinic/Apyrimidinic Endonuclease 1

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