Human base excision repair enzymes apurinic/apyrimidinic endonuclease1 (APE1), DNA polymerase   and poly(ADP-ribose) polymerase 1: interplay between strand-displacement DNA synthesis and proofreading exonuclease activity

Sukhanova, Maria V.; Ходырева, С. Н.; Лебедева, Н. А.; Prasad, Rajendra; Wilson, Samuel H.; Lavrik, Olga I.

doi:10.1093/nar/gki266

Cited by 128 publications

(78 citation statements)

References 48 publications

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“…Although these results comply with the suggested function of human UDG in controlling the rate of BER (71), our findings provide, to our knowledge, the first evidence of an important role of UDG in determining the BER subpathway. The T. acidophilum genome (51) contains neither a gene homologue to the XRCC1 (UniProtKB/Swiss-Prot accession number P18887) gene nor a gene homologue to a gene encoding a putative PARP1 or 2 protein (UniProtKB/Swiss-Prot accession numbers P09874 and Q9UGN5, respectively), which also has been suggested as a possible mammalian repair recruiter and regulator (15,20,67), so perhaps this organism uses UDG itself for such purposes. In this regard, we propose the following working hypothesis consisting of two scenarios.…”

Section: Discussionmentioning

confidence: 99%

Uracil-DNA Glycosylase of Thermoplasma acidophilumDirects Long-Patch Base Excision Repair, Which Is Promoted by Deoxynucleoside Triphosphates and ATP/ADP, into Short-Patch Repair

et al. 2011

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Hydrolytic deamination of cytosine to uracil in DNA is increased in organisms adapted to high temperatures. Hitherto, the uracil base excision repair (BER) pathway has only been described in two archaeons, the crenarchaeon Pyrobaculum aerophilum and the euryarchaeon Archaeoglobus fulgidus, which are hyperthermophiles and use single-nucleotide replacement. In the former the apurinic/apyrimidinic (AP) site intermediate is removed by the sequential action of a 5-acting AP endonuclease and a 5-deoxyribose phosphate lyase, whereas in the latter the AP site is primarily removed by a 3-acting AP lyase, followed by a 3-phosphodiesterase. We describe here uracil BER by a cell extract of the thermoacidophilic euryarchaeon Thermoplasma acidophilum, which prefers a similar short-patch repair mode as A. fulgidus. Importantly, T. acidophilum cell extract also efficiently executes ATP/ADP-stimulated long-patch BER in the presence of deoxynucleoside triphosphates, with a repair track of ϳ15 nucleotides. Supplementation of recombinant uracil-DNA glycosylase (rTaUDG; ORF Ta0477) increased the formation of short-patch at the expense of long-patch repair intermediates, and additional supplementation of recombinant DNA ligase (rTalig; Ta1148) greatly enhanced repair product formation. TaUDG seems to recruit AP-incising and -excising functions to prepare for rapid singlenucleotide insertion and ligation, thus excluding slower and energy-costly long-patch BER.In all cells, deamination of cytosine to uracil is only surpassed by depurination as the most common hydrolytic DNAdamaging event (38). While the apurinic/apyrimidinic (AP) site is primarily a cytotoxic lesion inhibiting replication or transcription, deaminated cytosines result in G ⅐ C to A ⅐ T transition mutations if they are not repaired before DNA synthesis. In addition, some dUTP escapes hydrolysis by dUTPase causing a certain amount of uracil introduced into DNA opposite adenine during replication (5, 32).Uracil is excised from DNA by a specific monofunctional uracil-DNA glycosylase (UDG) enzyme in virtually all organisms, including those living at the highest temperatures (22,33,47). After such enzyme-catalyzed, as well as spontaneous, base removal, a single nucleotide is reinserted by the sequential action of a 5Ј-acting AP endonuclease, 5Ј-deoxyribose phosphate (5Ј-dRP) lyase, DNA polymerase, and DNA ligase (22, 32), which constitute the short-patch mode of the base excision repair (BER) pathway. In eukaryotes, like mammals, the 5Ј-dRP lyase activity (35, 41) is a function of DNA polymerase ␤ (41, 62). BER is quantitatively the most important repair mechanism for the removal of spontaneously generated base modifications in DNA and is thus necessary to secure genomic integrity (38). The 5Ј-AP site remnant following strand incision blocks ligation, and when it is chemically modified in such a way that efficient removal by the 5Ј-dRP lyase is obstructed, polymerization will continue past one nucleotide and the downstream DNA strand is displaced. This long-patch mode of BER ...

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Section: Discussionmentioning

confidence: 99%

Uracil-DNA Glycosylase of Thermoplasma acidophilumDirects Long-Patch Base Excision Repair, Which Is Promoted by Deoxynucleoside Triphosphates and ATP/ADP, into Short-Patch Repair

et al. 2011

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“…It was suggested that interaction between APE and dRP-containing intermediates could assist in SN-BER versus LP-BER subpathway choice, and a large excess of APE was found to stimulate Pol ␤ strand-displacement synthesis during LP-BER (46). This stimulation was inhibited by the addition of PARP-1 (46).…”

Section: Discussionmentioning

confidence: 99%

Coordination of Steps in Single-nucleotide Base Excision Repair Mediated by Apurinic/Apyrimidinic Endonuclease 1 and DNA Polymerase β

Liu

Prasad

Beard

et al. 2007

Journal of Biological Chemistry

137

120

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The individual steps in single-nucleotide base excision repair (SN-BER) are coordinated to enable efficient repair without accumulation of cytotoxic DNA intermediates. The DNA transactions and various proteins involved in SN-BER of abasic sites are well known in mammalian systems. Yet, despite a wealth of information on SN-BER, the mechanism of step-by-step coordination is poorly understood. In this study we conducted experiments toward understanding step-by-step coordination during BER by comparing DNA binding specificities of two major human SN-BER enzymes, apurinic/aprymidinic endonuclease 1 (APE) and DNA polymerase ␤ (Pol ␤). It is known that these enzymes do not form a stable complex in solution. For each enzyme, we found that DNA binding specificity appeared sufficient to explain the sequential processing of BER intermediates. In addition, however, we identified at higher enzyme concentrations a ternary complex of APE⅐Pol ␤⅐DNA that formed specifically at BER intermediates containing a 5-deoxyribose phosphate group. Formation of this ternary complex was associated with slightly stronger Pol ␤ gap-filling and much stronger 5-deoxyribose phosphate lyase activities than was observed with the Pol ␤⅐DNA binary complex. These results indicate that step-bystep coordination in SN-BER can rely on DNA binding specificity inherent in APE and Pol ␤, although coordination also may be facilitated by APE⅐Pol ␤⅐DNA ternary complex formation with appropriate enzyme expression levels or enzyme recruitment to sites of repair.

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“…This localization is abolished in the presence of antioxidants (12), suggesting that ROS are the driving force of this localization. Another interesting APE1 function, connected to its capacity to bind to SSB, is that of inhibiting the same binding by PARP1, with consequent inactivation of the poly-ADP-ribosylation and prevention of necrosis (121).…”

Section: Dna Repair Activity Of Ape1mentioning

confidence: 99%

The Many Functions of APE1/Ref-1: Not Only a DNA Repair Enzyme

Tell

Quadrifoglio

Tiribelli

et al. 2009

Antioxidants & Redox Signaling

441

412

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APE1/Ref-1 (APE1), the mammalian ortholog of Escherichia coli Xth, and a multifunctional protein possessing both DNA repair and transcriptional regulatory activities, has a pleiotropic role in controlling cellular response to oxidative stress. APE1 is the main apurinic/apyrimidinic endonuclease in eukaryotic cells, playing a central role in the DNA base excision repair pathway of all DNA lesions (uracil, alkylated and oxidized, and abasic sites), including single-strand breaks, and has also cotranscriptional activity by modulating genes expression directly regulated by either ubiquitous (i.e., AP-1, Egr-1, NF-B, p53, and HIF) and tissue specific (i.e., PEBP-2, Pax-5 and -8, and TTF-1) transcription factors. In addition, it controls the intracellular redox state by inhibiting the reactive oxygen species (ROS) production. At present, information is still inadequate regarding the molecular mechanisms responsible for the coordinated control of its several activities. Both expression and/or subcellular localization are altered in several metabolic and proliferative disorders such as in tumors and aging. Here, we have attempted to coalesce the most relevant information concerning APE1's different functions in order to shed new light and to focus current and future studies to fully understand this unique molecule that is acquiring more and more interest and translational relevance in the field of molecular medicine. Antioxid. Redox Signal. 11,[601][602][603][604][605][606][607][608][609][610][611][612][613][614][615][616][617][618][619]

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Human base excision repair enzymes apurinic/apyrimidinic endonuclease1 (APE1), DNA polymerase and poly(ADP-ribose) polymerase 1: interplay between strand-displacement DNA synthesis and proofreading exonuclease activity

Cited by 128 publications

References 48 publications

Uracil-DNA Glycosylase of Thermoplasma acidophilumDirects Long-Patch Base Excision Repair, Which Is Promoted by Deoxynucleoside Triphosphates and ATP/ADP, into Short-Patch Repair

Uracil-DNA Glycosylase of Thermoplasma acidophilumDirects Long-Patch Base Excision Repair, Which Is Promoted by Deoxynucleoside Triphosphates and ATP/ADP, into Short-Patch Repair

Coordination of Steps in Single-nucleotide Base Excision Repair Mediated by Apurinic/Apyrimidinic Endonuclease 1 and DNA Polymerase β

The Many Functions of APE1/Ref-1: Not Only a DNA Repair Enzyme

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