An exonucleolytic activity of human apurinic/apyrimidinic endonuclease on 3′ mispaired DNA

Chou, Kai Ming; Cheng, Yung Chi

doi:10.1038/415655a

Cited by 224 publications

(204 citation statements)

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“…32 In addition to AP endonuclease activity, APE1 also possesses 3 0 -phosphodiesterase, 3 0 -phosphatase and 3 0 -5 0 -exonuclease functions specific for the 3 0 termini of internal nicks and gaps in DNA. [33][34][35] The present study found that APE1 was strongly expressed in LOVO cells and the expression of APE1 was increased by irradiation, probably representing an early event in the cell response to irradiation because of its role in DNA BER, and promoting radioresistance. Ad5/ F35-APE1 siRNA inhibited APE1 expression and AP endonuclease activity in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 87%

Chimeric adenoviral vector Ad5/F35-mediated APE1 siRNA enhances sensitivity of human colorectal cancer cells to radiotherapy in vitro and in vivo

Wang

et al. 2008

Cancer Gene Ther

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Apurinic/apyrimidinic endonuclease (APE1), a bifunctional AP endonuclease/redox factor, is important in DNA repair and redox signaling, may be associated with radioresistance. Here we investigate whether targeted inhibition of APE1 can sensitize tumor cells to irradiation in vitro and in vivo. We first constructed chimeric adenoviral vector Ad5/F35 carrying human APE1 siRNA (Ad5/ F35-APE1 siRNA). The infectivity of chimeric Ad5/F35 to LOVO colon cancer cells was greater than that of Ad5. APE1 was strongly expressed and nuclear factor kB (NF-kB), a downstream molecule of APE1, known as a radioresistance factor, was constitutively active in LOVO cells. Infection of LOVO cells with Ad5/F35-APE1 siRNA resulted in a dose-dependent decrease of APE1 protein and AP endonuclease activity in vitro. Ad5/F35-APE1 siRNA significantly enhanced sensitivity of LOVO cells to irradiation in clonogenic survival assays, associated with increased cell apoptosis. The APE1 expression in LOVO cells was induced by irradiation in a dose-dependent manner, accompanied with the enhancement of DNA-binding activity of NF-kB and Ad5/F35-APE1 siRNA effectively inhibited constitutive and irradiation-induced APE1 expression and NF-kB activation. In a subcutaneous nude mouse colon cancer model, Ad5/F35-APE1 siRNA (5 Â 10 8 IU, intratumoral injection) inhibited the expression of APE1 protein in LOVO xenografts, and significantly enhanced inhibition of tumor growth by irradiation. In conclusion, APE1 may be involved as one of the radioresistance factors, and targeted inhibition of APE1 shows an effective means of enhancing tumor sensitivity to radiotherapy.

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Section: Discussionmentioning

confidence: 87%

Chimeric adenoviral vector Ad5/F35-mediated APE1 siRNA enhances sensitivity of human colorectal cancer cells to radiotherapy in vitro and in vivo

Wang

et al. 2008

Cancer Gene Ther

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“…76 APE1 has been suggested to act as a proofreading enzyme for mistakes made by Pol β during BER gap filling synthesis. 77 Several APE1 variants in the general population have functional phenotypes. The APE 1 gene maps to chromosome 14q11.2-q12.…”

Section: Ape1 Alterations and Expression Levels May Be Linked To Cancmentioning

confidence: 99%

Is Base Excision Repair a Tumor Suppressor Mechanism?

Sweasy¹,

Lang²,

DiMaio³

2006

Cell Cycle

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The base excision repair pathway is critical for the removal of oxidized and methylated bases from the DNA. Much of this DNA damage arises endogenously, as a result of oxygen metabolism. Several proteins including DNA glycosylases, the APE1 endonuclease, DNA polymerase β and DNA ligase, act in a highly regulated and coordinated manner during base excision repair to excise the base adducts from the DNA and restore the normal DNA sequence. Both germline and tumor-associated variants of genes encoding these proteins have been identified in humans. In many cases, the protein variant has been shown to have properties that could contribute to the development of cancer, suggesting that base excision repair acts as a tumor suppressor mechanism in humans. Limited epidemiological studies are consistent with this view. Our review of the literature indicates that additional laboratory and epidemiological studies of the role of base excision repair in cancer etiology is warranted.

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confidence: 99%

“…APEs from both families are also capable of acting as 3′ f 5′ exonucleases at nicks (16,17); because this activity is most efficient for nicks containing a 3′ mismatched base pair, it is speculated to enhance the fidelity of DNA repair by providing, in trans, the proofreading activity that is typically absent in repair polymerases (16). Most recently, APEs from both protein families have been shown to catalyze nucleotide incision repair (NIR) in which, bypassing the step of base removal by a DNA glycosylase, the APE directly incises the sugar-phosphate backbone 5′ to a nucleotide containing a damaged base 3 to generate a single-nucleotide gap flanked by a 3′-hydroxyl and a 5′-"dangling nucleotide"-which can subsequently be removed by a flap endonuclease 1 (FEN1)-like activity (18)(19)(20)(21).…”

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confidence: 99%

Contributions of an Endonuclease IV Homologue to DNA Repair in the African Swine Fever Virus

Lamarche

Tsai

2006

Biochemistry

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: We recently demonstrated that African swine fever virus DNA polymerase X (Pol X) is extremely error-prone during single-nucleotide gap-filling and that the downstream ASFV DNA ligase seals 3′ mismatched nicks with high efficiency. To further assess the credence of our hypothesis that these proteins may promote viral diversification by functioning within the context of an aberrant DNA repair pathway, herein we characterize the third protein expected to function in this system, a putative AP endonuclease (APE). Assays of the purified protein using oligonucleotide substrates unequivocally establish canonical APE activity, 3′-phosphatase and 3′-phosphodiesterase activities (in the context of a singlenucleotide gap), 3′ f 5′ exonuclease activity (in the context of a nick), and nucleotide incision repair activity against 5,6-dihydrothymine. The 3′ f 5′ exonuclease activity is shown to be highly dependent upon the identity of the nascent 3′ base pair and to be inhibited when 2-deoxyribose-5-phosphate, rather than phosphate, constitutes the 5′ moiety of the nick. ASFV APE retains activity when assayed in the presence of EDTA but is inactivated by incubation with 1,10-phenanthroline in the absence of a substrate, suggesting that it is an endonuclease IV homologue possessing intrinsic metal cofactors. The activities of ASFV APE, when considered alongside those of Pol X and ASFV DNA ligase, provide an enhanced understanding of (i) the types of damage that are likely to be sustained by the viral genome and (ii) the mechanisms by which the minimalist ASFV DNA repair pathway, consisting of just these three proteins, contributes to the fitness of the virus.Apurinic/apyrimidinic (AP) 1 sites, generated either by DNA glycosylase-mediated or spontaneous base loss, can be both mutagenic (1, 2) and cytotoxic (3) and are among the most abundant types of damage found in DNA (4). Although they can be processed by AP lyases, which cleave 3′ to the lesion by a -elimination mechanism to generate a single-nucleotide gap flanked by 5′-phosphate and a 3′-polymerase-blocking R, -unsaturated aldehyde (5-7), AP sites are likely to be processed predominantly by AP endonucleases (8), which catalyze hydrolysis of the sugarphosphate backbone 5′ of the lesion to generate a singlenucleotide gap flanked by a polymerase-usable 3′-hydroxyl and 5′-2-deoxyribose-5-phosphate (5′-dRP) (7). Two families of APEs have been identified to date; these consist of proteins with homology to Escherichia coli exonuclease III 2 and proteins with homology to E. coli endonuclease IV. While the reaction that these proteins catalyze is identical, they differ dramatically in both tertiary structure and mechanisms of catalysis (9). Whereas exonuclease III displays a fourlayered R, -sandwich fold and employs a single readily dissociatable magnesium ion (9, 10), endonuclease IV is an R 8 8 TIM barrel that utilizes three tightly bound zinc ions (9,11).In addition to their APE activities, both exonuclease III and endonuclease IV (and their respective homologues) pos...

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An exonucleolytic activity of human apurinic/apyrimidinic endonuclease on 3′ mispaired DNA

Cited by 224 publications

References 23 publications

Chimeric adenoviral vector Ad5/F35-mediated APE1 siRNA enhances sensitivity of human colorectal cancer cells to radiotherapy in vitro and in vivo

Chimeric adenoviral vector Ad5/F35-mediated APE1 siRNA enhances sensitivity of human colorectal cancer cells to radiotherapy in vitro and in vivo

Is Base Excision Repair a Tumor Suppressor Mechanism?

Contributions of an Endonuclease IV Homologue to DNA Repair in the African Swine Fever Virus

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