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

Bennett, Richard A. O.; Wilson, David M.; Wong, David G.; Demple, Bruce

doi:10.1073/pnas.94.14.7166

Cited by 331 publications

(219 citation statements)

References 31 publications

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“…However, the current dogma of BER requires that BER proteins function in a highly coordinated series of complex protein-protein and protein-DNA interactions to minimize the formation of toxic DNA repair intermediates. For example, APE has been shown to interact with ␤-pol, facilitating its loading onto AP DNA, and stimulates its rate-determining dRP excision activity (31). Here we present data demonstrating that reduced APE results in decreased AP site DNA binding activity, which may consequently affect BER activity by altering the formation of a repair complex on AP lesions.…”

Section: Discussionmentioning

confidence: 50%

“…For example, x-ray cross-complementing protein (XRCC1), a protein with no known enzymatic activity, functions as both a scaffold protein and modulator of BER via functional and physical interaction with APE, bridging the incision and nick-sealing steps of BER (30). APE has been shown also to interact with ␤-pol, recruiting it to the incised AP site and enhancing its rate-limiting dRPase activity (31); this activity is also believed to be involved in the repair of oxidative base lesions (32). The functional importance of ␤-pol in oxidative damage repair may be due to the interaction of APE with bifunctional DNA glycosylases responsible for recognizing and removing these lesions.…”

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confidence: 99%

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Apurinic/Apyrimidinic Endonuclease (APE/REF-1) Haploinsufficient Mice Display Tissue-specific Differences in DNA Polymerase β-Dependent Base Excision Repair

Raffoul

Cabelof

Nakamura

et al. 2004

Journal of Biological Chemistry

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Apurinic/apyrimidinic (AP) endonuclease (APE) is a multifunctional protein possessing both DNA repair and redox regulatory activities. In base excision repair (BER), APE is responsible for processing spontaneous, chemical, or monofunctional DNA glycosylase-initiated AP sites via its 5 -endonuclease activity and 3 -"endtrimming" activity when processing residues produced as a consequence of bifunctional DNA glycosylases. In this study, we have fully characterized a mammalian model of APE haploinsufficiency by using a mouse containing a heterozygous gene-targeted deletion of the APE gene (Apex ؉/؊ ). Our data indicate that Apex ؉/؊ mice are indeed APE-haploinsufficient, as exhibited by a 40 -50% reduction (p < 0.05) in APE mRNA, protein, and 5 -endonuclease activity in all tissues studied. Based on gene dosage, we expected to see a concomitant reduction in BER activity; however, by using an in vitro G:U mismatch BER assay, we observed tissue-specific alterations in monofunctional glycosylase-initiated BER activity, e.g. liver (35% decrease, p < 0.05), testes (55% increase, p < 0.05), and brain (no significant difference). The observed changes in BER activity correlated tightly with changes in DNA polymerase ␤ and AP site DNA binding levels. We propose a mechanism of BER that may be influenced by the redox regulatory activity of APE, and we suggest that reduced APE may render a cell/tissue more susceptible to dysregulation of the polymerase ␤-dependent BER response to cellular stress.Apurinic/apyrimidinic (AP) 1 endonuclease (APE) is a multifunctional protein involved in the maintenance of genomic integrity and in the regulation of gene expression. After the initial discovery in Escherichia coli (1), APE was purified from calf thymus DNA and extensively characterized as an endonuclease that cleaves the backbone of double-stranded DNA containing AP sites (2, 3). APE homologues were subsequently identified and characterized in many organisms, including yeast as APN1 (4), mice as Apex (5, 6), and humans as HAP1 (7). In addition to its major 5Ј-endonuclease activity, APE also expresses minor 3Ј-phosphodiesterase, 3Ј-phosphatase, and 3Ј 3 5Ј-exonuclease activities (8), the biological significance of which is controversial (9). Independent of its discovery as a DNA repair protein, APE was also characterized as REF-1, for redox factor-1, a redox activator of cellular transcription factors (10 -12). Although the molecular detail of APE redox activity is still unclear (13), the discovery of APE as a regulator of transcriptional activity may underscore the importance of its involvement in cellular stress-response pathways.APE is the primary enzyme responsible for recognition and incision of non-coding AP sites in DNA arising as a consequence of spontaneous, chemical, or DNA glycosylase-mediated hydrolysis of the N-glycosyl bond initiated by the base excision repair (BER) pathway. These lesions are particularly common, arising at the rate of ϳ50,000 -200,000 AP sites per cell per day under normal physiological conditions (14,...

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Section: Discussionmentioning

confidence: 50%

mentioning

confidence: 99%

Apurinic/Apyrimidinic Endonuclease (APE/REF-1) Haploinsufficient Mice Display Tissue-specific Differences in DNA Polymerase β-Dependent Base Excision Repair

Raffoul

Cabelof

Nakamura

et al. 2004

Journal of Biological Chemistry

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“…Table I Possible entry mechanisms of a unified base excision repair model [12,17,23,63,66,75,88,113,119,128,129,149,150,[152][153][154][155][156][157] LigI…”

Section: Fig 2 a Unified Model Of Bermentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

378

373

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Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or longpatch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neurodegeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multiprotein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER proteinprotein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

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“…For example, APE1 interacts with and stimulates certain catalytic activities of Pol β. [97][98][99] The interaction of XRCC1 with Pol β is required for efficient BER and for the recruitment of the DNA ligase IIIα-XRCC1 complex to the DNA nick. 100,101 Thus, polymorphisms that result in amino acid changes that disrupt or alter the interaction of APE1 with Pol β or Pol β with XRCC1 could result in deficient or aberrant BER and ultimately lead to cancer.…”

Section: Linkage Between Aberrant Ber and Cancermentioning

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

Abstract: ABSTRACT

Cited by 331 publications

References 31 publications

Apurinic/Apyrimidinic Endonuclease (APE/REF-1) Haploinsufficient Mice Display Tissue-specific Differences in DNA Polymerase β-Dependent Base Excision Repair

Apurinic/Apyrimidinic Endonuclease (APE/REF-1) Haploinsufficient Mice Display Tissue-specific Differences in DNA Polymerase β-Dependent Base Excision Repair

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Is Base Excision Repair a Tumor Suppressor Mechanism?

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