AP endonuclease and poly(ADP-ribose) polymerase-1 interact with the same base excision repair intermediate

Cistulli, Cheryl A.; Lavrik, Olga I.; Prasad, Rajendra; Hou, Esther W.; Wilson, Samuel H.

doi:10.1016/j.dnarep.2003.09.012

Cited by 82 publications

(47 citation statements)

References 42 publications

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“…This stimulation was inhibited by the addition of PARP-1 (46). Additionally, APE was able to compete with and block PARP-1 binding to the dRP-containing intermediate and, hence, may interfere with the role of PARP-1 as a stimulatory factor in LP-BER (53). Our finding that the APE⅐Pol ␤⅐DNA ternary complex can form solely on BER intermediates containing the dRP group was consistent with the APE binding preference for dRP group-containing molecules.…”

Section: Discussionsupporting

confidence: 77%

“…Binding of APE to its incision product is well known (42,53,56), and the functional significance of this binding has been a topic of investigation. 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).…”

Section: Discussionmentioning

confidence: 99%

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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

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136

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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Section: Discussionsupporting

confidence: 77%

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

Self Cite

136

120

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“…The binding of PARP1 depends on the DNA substrate (Horton and Wilson, 2013). PARP1 preferentially binds directly to base excision repair-intermediates with a 59-dRP rather than to 59-phosphate ends (Cistulli et al, 2004). This can explain the formation of PARP-DNA complexes at SSBs induced by temozolomide and suggests that combining temozolomide with a potent PARP-trapping agent, such as olaparib, is more rational than combining it with a potent catalytic inhibitor with lower PARP-trapping potency, such as veliparib (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Rationale for Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Combination Therapy with Camptothecins or Temozolomide Based on PARP Trapping versus Catalytic Inhibition

Murai

Zhang

Morris

et al. 2014

J Pharmacol Exp Ther

237

194

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We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors exert their cytotoxicity primarily by trapping PARP-DNA complexes in addition to their NAD 1 -competitive catalytic inhibitory mechanism. PARP trapping is drug-specific, with olaparib exhibiting a greater ability than veliparib, whereas both compounds are potent catalytic PARP inhibitors. Here, we evaluated the combination of olaparib or veliparib with therapeutically relevant DNA-targeted drugs, including the topoisomerase I inhibitor camptothecin, the alkylating agent temozolomide, the cross-linking agent cisplatin, and the topoisomerase II inhibitor etoposide at the cellular and molecular levels. We determined PARP-DNA trapping and catalytic PARP inhibition in genetically modified chicken lymphoma DT40, human prostate DU145, and glioblastoma SF295 cancer cells. For camptothecin, both PARP inhibitors showed highly synergistic effects due to catalytic PARP inhibition, indicating the value of combining either veliparib or olaparib with topoisomerase I inhibitors. On the other hand, for temozolomide, PARP trapping was critical in addition to catalytic inhibition, consistent with the fact that olaparib was more effective than veliparib in combination with temozolomide. For cisplatin and etoposide, olaparib only showed no or a weak combination effect, which is consistent with the lack of involvement of PARP in the repair of cisplatin-and etoposide-induced lesions. Hence, we conclude that catalytic PARP inhibitors are highly effective in combination with camptothecins, whereas PARP inhibitors capable of PARP trapping are more effective with temozolomide. Our study provides insights in combination treatment rationales for different PARP inhibitors.

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“…This is exemplified by the combination of PARP inhibitors with the alkylating agent TMZ. TMZ induces two types of DNA lesions: 1) O 6 -methylguanine adducts, which cause DNA DSB and apoptosis-cells with defective mismatch repair pathway or cells with functional O 6 -methylguanine methyltransferase are resistant to this mechanism; and 2) N 7 -methylguanine (N 7 mG) and N 3 -methyladenine (N 3 mA) DNA adducts, which account for ∼90% of all methylation events caused by TMZ but are nonlethal in most normal cells and tumor cells, because they are readily repaired by BER (Sarkaria et al, 2008;Zhang et al, 2012 (Cistulli et al, 2004;Horton and Wilson, 2013a,b;Horton et al, 2014). In fact, 59-deoxyribose phosphate is a preferred substrate for PARP trapping (Murai et al, 2014b;Smith et al, 2015).…”

Section: Trapping Parpmentioning

confidence: 99%

Trapping Poly(ADP-Ribose) Polymerase

Shen

Aoyagi-Scharber

Wang

2015

J Pharmacol Exp Ther

181

186

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Recent findings indicate that a major mechanism by which poly (ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells. In this article, we review the available data on molecular interactions between these clinical-stage PARP inhibitors and PARP proteins, and discuss how their biologic differences might be explained by the trapping mechanism. We also discuss how to use the PARP-trapping mechanism to guide the development of PARP inhibitors as a new class of cancer therapy, both for singleagent and combination treatments.

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AP endonuclease and poly(ADP-ribose) polymerase-1 interact with the same base excision repair intermediate

Cited by 82 publications

References 42 publications

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

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

Rationale for Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Combination Therapy with Camptothecins or Temozolomide Based on PARP Trapping versus Catalytic Inhibition

Trapping Poly(ADP-Ribose) Polymerase

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