2005
DOI: 10.1158/0008-5472.can-05-0715
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The Role of Base Excision Repair in the Sensitivity and Resistance to Temozolomide-Mediated Cell Death

Abstract: DNA-alkylating agents have a central role in the curative therapy of many human tumors; yet, resistance to these agents limits their effectiveness. The efficacy of the alkylating agent temozolomide has been attributed to the induction of O 6 -MeG, a DNA lesion repaired by the protein O 6 -methylguanine-DNA methyltransferase (MGMT). Resistance to temozolomide has been ascribed to elevated levels of MGMT and/ or reduced mismatch repair. However, >80% of the DNA lesions induced by temozolomide are N-methylated ba… Show more

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Cited by 215 publications
(221 citation statements)
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“…We have notified ATCC to change the description for this cell line and will point out, as indicated in Table I that a second matched pair of MEFs are available from ATCC each of which are WT for pol ι. The alkylation sensitivity of pol β deficient cells is not in questionseveral additional reports have confirmed this observation using the matched pairs listed in Table I that are WT for pol ι, including the 36.3 and 38 4 matched pair [36,55] and the 92TAg and 88TAg matched pair [42,44] as well as pol β deficiency mediated by RNA interference [44,65] and many other studies from other laboratories. It remains to be determined if these double null cells have an increased sensitivity to alkylating agents and most importantly, if complementation with mouse pol ι effects a change as well.…”
mentioning
confidence: 70%
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“…We have notified ATCC to change the description for this cell line and will point out, as indicated in Table I that a second matched pair of MEFs are available from ATCC each of which are WT for pol ι. The alkylation sensitivity of pol β deficient cells is not in questionseveral additional reports have confirmed this observation using the matched pairs listed in Table I that are WT for pol ι, including the 36.3 and 38 4 matched pair [36,55] and the 92TAg and 88TAg matched pair [42,44] as well as pol β deficiency mediated by RNA interference [44,65] and many other studies from other laboratories. It remains to be determined if these double null cells have an increased sensitivity to alkylating agents and most importantly, if complementation with mouse pol ι effects a change as well.…”
mentioning
confidence: 70%
“…In the absence of pol β (in MEFs), cells are unable to efficiently repair the highly toxic 5′dRP moiety and therefore are hypersensitive to different types of alkylating agents such as methylmethane sulfonate, N-methyl-N-nitrosourea and N-methyl-N′-nitro-N-nitrosoguanidine [28,36,42,44,55], the thymidine analog 5-hydroxymethyl-2′ -deoxyuridine [40] as well as the therapeutic agent temozolomide [40,44]. Recently, it was also demonstrated that in addition to pol β, DNA polymerase λ (pol λ) and DNA polymerase ι (pol ι), as well as the mitochondrial polymerase pol γ have 5′dRP lyase activity and can function (in vitro) in the removal of the 5′ dRP group that arises during BER [53,[57][58][59][60][61].…”
Section: Nih Public Accessmentioning
confidence: 99%
“…This mechanism or process of complex formation appears to provide an increase in specificity and efficiency to the BER pathway, thereby facilitating the maintenance of genome integrity by preventing the accumulation of highly toxic repair intermediates [83]. Decreased concentrations of just one protein within this pathway could significantly alter the balance of complex formation, resulting in reduced repair capacity and an increased exposure to toxic BER intermediates, such as has been observed in pol ß deficiency in mouse cells [79,[91][92][93], in animal models [94] and in human cells [62].…”
Section: Ber Protein Post-translational Modificationsmentioning
confidence: 98%
“…Interestingly, both DNA polymerase lambda (pol λ) and DNA polymerase iota (pol ι) encode a 5'dRP lyase function [77,78]. Each has been shown capable of removing the 5'dRP lesion subsequent to APE1 strand cleavage [77,78] [79], confirming that pol ß is the predominant activity in mouse embryonic fibroblasts (MEFs) [79]. However, it was demonstrated that pol λ deficient MEFs are sensitive to hydrogen peroxide [80], suggesting that the participation of either pol λ or pol ι in BER may be lesion specific.…”
Section: Gap Tailoringmentioning
confidence: 99%
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