The major human AP endonuclease (Ape1) is involved in the nucleotide incision repair pathway

Gros, Laurent; Ищенко, А. А.; Ide, Hiroshi; Elder, Rhoderick H.; Saparbaev, Murat

doi:10.1093/nar/gkh165

Cited by 184 publications

(225 citation statements)

References 52 publications

Supporting

Mentioning

219

Contrasting

Order By: Relevance

“…Intrinsic metals play a critical role in the bacterial, yeast, and human AP endonucleases (3,5). We examined the metal content of the WT and mutant Nfo proteins by using two different Zn detectors, FluoZin-3, and 4-(2-pyridylazo)resorcinol (PAR).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Uncoupling of the base excision and nucleotide incision repair pathways reveals their respective biological roles

Ищенко

Deprez

Maksimenko

et al. 2006

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

View full text Add to dashboard Cite

The multifunctional DNA repair enzymes apurinic͞apyrimidinic (AP) endonucleases cleave DNA at AP sites and 3 -blocking moieties generated by DNA glycosylases in the base excision repair pathway. Alternatively, in the nucleotide incision repair (NIR) pathway, the same AP endonucleases incise DNA 5 of a number of oxidatively damaged bases. At present, the physiological relevance of latter function remains unclear. Here, we report genetic dissection of AP endonuclease functions in base excision repair and NIR pathways. Three mutants of Escherichia coli endonuclease IV (Nfo), carrying amino acid substitutions H69A, H109A, and G149D have been isolated. All mutants were proficient in the AP endonuclease and 3 -repair diesterase activities but deficient in the NIR. Analysis of metal content reveals that all three mutant proteins have lost one of their intrinsic zinc atoms. Expression of the nfo mutants in a repair-deficient strain of E. coli complemented its hypersensitivity to alkylation but not to oxidative DNA damage. The differential drug sensitivity of the mutants suggests that the NIR pathway removes lethal DNA lesions generated by oxidizing agents. To address the physiological relevance of the NIR pathway in human cells, we used the fluorescence quenching mechanism of molecular beacons. We show that in living cells a major human AP endonuclease, Ape1, incises DNA containing ␣-anomeric 2 -deoxyadenosine, indicating that the intracellular environment supports NIR activity. Our data establish that NIR is a distinct and separable function of AP endonucleases essential for handling lethal oxidative DNA lesions. apurinic͞apyrimidinic endonuclease ͉ oxidative DNA damage ͉ tert-butyl hydroperoxide ͉ 3Ј-blocking groups ͉ ␣-anomeric 2Ј-deoxyadenosine

show abstract

Section: Resultsmentioning

confidence: 99%

“…Obviously, this latter mechanistic feature is distinct from DNA glycosylase-mediated BER. We have proposed that NIR participates in vivo in the removal of lethal oxidative DNA base damage (3). However, at present the physiological relevance of the NIR pathway remains unclear.…”

mentioning

confidence: 99%

Uncoupling of the base excision and nucleotide incision repair pathways reveals their respective biological roles

Ищенко

Deprez

Maksimenko

et al. 2006

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

View full text Add to dashboard Cite

show abstract

“…Strikingly, APE1, thought to be limited to cleavage of abasic sites in intact, double-stranded DNA, has been reported to recognize and incise at certain base damages (e.g., 5,6-dihydro-2¢-deoxyuridine, 5,6-dihydrothymidine, 5-hydroxy-2¢-deoxyuridine, a-2¢-deoxyadenosine, and a-thymidine adducts), generating single-strand break ends with a 3¢-hydroxyl and a 5¢-dangling modified nucleotide (65). Distinct from its AP endonuclease function, this activity-proposed to initiate a corrective response termed nucleotide incision repair (NIR) that would serve as a back-up for the more classical glycosylase-initiated BER pathway-is most active at low MgCl 2 and KCl concentrations, at a pH range of 6.4 to 6.8.…”

Section: Nucleotide Incision Repairmentioning

confidence: 99%

Human Apurinic/Apyrimidinic Endonuclease 1

2014

Antioxidants & Redox Signaling

228

221

View full text Add to dashboard Cite

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,

show abstract

“…For example, APE1 has been found to initiate DNA glycosylase-independent repair of oxidized cytosines [20][21][22]. This alternate repair pathway has been defined as Nucleotide Incision Repair (NIR), yet can also be considered a minor sub-pathway of BER with a unique APE1-mediated repair initiation event.…”

Section: Introduction Of a Unifying Ber Modelmentioning

confidence: 99%

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

Almeida¹,

Sobol²

2007

DNA Repair

387

374

View full text Add to dashboard Cite

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.

show abstract

The major human AP endonuclease (Ape1) is involved in the nucleotide incision repair pathway

Cited by 184 publications

References 52 publications

Uncoupling of the base excision and nucleotide incision repair pathways reveals their respective biological roles

Uncoupling of the base excision and nucleotide incision repair pathways reveals their respective biological roles

Human Apurinic/Apyrimidinic Endonuclease 1

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

Contact Info

Product

Resources

About