DNA Mismatch Binding and Incision at Modified Guanine Bases by Extracts of Mammalian Cells: Implications for Tolerance to DNA Methylation Damage

Griffin, Shaun; Branch, Pauline; Xu, Yao−Zhong; Karran, Peter

doi:10.1021/bi00182a006

Cited by 92 publications

(82 citation statements)

References 38 publications

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“…Loss of DNA mismatch repair has been reported to produce drug resistance, directly by impairing the ability of the cell to detect adducts in its DNA that mimic base mismatches, and indirectly by increased gene mutation rates, leading to a mutator phenotype. For example, loss of mismatch repair causes high-level resistance to the antimetabolite 6-thioguanine, 20 moderate levels of resistance to the methylating agent N-methyl-NЈ-nitro-N-nitrosoguanidine 21 and low-level resistance to the platinum-containing drugs cisplatin and carboplatin. 7 All these agents cause cell death via apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Resistance to topoisomerase poisons due to loss of DNA mismatch repair

et al. 2001

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Sporadic breast carcinomas demonstrate microsatellite instability, reflecting the presence of DNA mismatch repairdeficient cells, in about one fourth of cases at the time of diagnosis. Loss of DNA mismatch repair has been reported to result in resistance not only to cisplatin and alkylating agents but also to the topoisomerase II poison doxorubicin, suggesting an association between DNA mismatch repair and topoisomerase II poison-induced cytotoxicity. Our study investigates the relationship between loss of MSH2 or MLH1 function and sensitivity to the topoisomerase I and II poisons, and to the taxanes, 2 classes of cytotoxic drugs commonly used in breast cancer. Two pairs of cell lines proficient and deficient in mismatch repair due to loss of either MSH2 or MLH1 function were used. Loss of either MSH2 or MLH1 function resulted in resistance to the topoisomerase II poisons doxorubicin, epirubicin and mitoxantrone, whereas only loss of MLH1 function was associated with low-level resistance to the topoisomerase I poisons camptothecin and topotecan. In contrast, there was no resistance to docetaxel and paclitaxel. Our data support the hypothesis that both MSH2 and MLH1 are involved in topoisomerase II poisonmediated cytotoxicity, whereas only MLH1 is involved in topoisomerase I poison-mediated cytotoxicity. Since our study shows that loss of DNA mismatch repair does not result in resistance to the taxanes, these drugs can be recommended for use in breast cancer deficient in mismatch repair.

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Section: Discussionmentioning

confidence: 99%

“…Previously, it was reported that loss of MLH1 results in resistance to 6-thioguanine 20 and 5-fluorouracil. 8 Gemcitabine is incorporated as difluorodeoxycytidine-monophosphate (dFdCMP), resulting in inhibition of chain elongation due to the inability of dFdCMP to be excised by exonucleases.…”

Section: Discussionmentioning

confidence: 99%

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

et al. 2001

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“…That resistance to temozolomide in this cell line was not dependent upon AGT activity was confirmed with both single and repeat dosing studies, in which depletion of AGT by 06-BG did not afford an increase in temozolomide cytotoxicity (Figures 4 and 6). This 'tolerance' to methylation may be attributable to loss of the mismatch repair pathway, which would normally generate DNA strand breaks and thereby induce cell death during the futile attempt to find a complementary base for o6-methylguanine (Griffin et al, 1994 Modrich, 1986): hMSH2 (Fishel et al, 1993) and GTBP/pl60 (Drummond et al, 1995;Palombo et al, 1995). This structure interacts with another heterodimer consisting of hPMS2 and hMLH1 proteins (Li and Modrich, 1995), which are homologues of the E. coli MutL repair protein (Grilley et al, 1989).…”

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confidence: 99%

Potentiation of temozolomide and BCNU cytotoxicity by O6-benzylguanine: a comparative study in vitro

Wedge

Porteus²,

May³

et al. 1996

Br J Cancer

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Depletion of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) with O(6)-benzylguanine (O(6)-BG) has been widely shown to enhance 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) activity. This study aimed to determine whether temozolomide, a methylating imidazotetrazinone, would similarly benefit from combination with O(6)-BG. Seven human cell lines were examined with AGT activities ranging from <6 fmol mg-1 protein to >700 fmol mg-1 protein. Comparisons with BCNU were made on both single and multiple dosing schedules, since temozolomide cytotoxicity is highly schedule dependent. In single-dose potentiation studies, cells were preincubated with 100 microM O(6)-BG for 1 h, a treatment found to deplete AGT activity by >90% for 24 h. No potentiation of either temozolomide or BCNU cytotoxicity was observed in two glioblastoma cell lines with <6 fmol mg-1 protein AGT. In all other cell lines studied potentiation of BCNU toxicity by O(6)-BG was between 1.6- and 2.3-fold and exceeded that of temozolomide (1.1- to 1.7-fold). The magnitude of this potentiation was unrelated to AGT activity and the relative potentiation of temozolomide and BCNU cytotoxicity was found to be highly variable between cell lines. In multiple dosing studies two colorectal cell lines (Mawi and LS174T) were treated with temozolomide or BCNU at 24 h intervals for up to 5 days, with or without either 100 microM O(6)-BG for 1 h or 1 microM O(6)-BG for 24 h, commencing 1 h before alkylating treatment. Extended treatment with 1 microM O(6)-BG produced greater potentiation than intermittent treatment with 100 microM O(6)-BG. Potentiation of temozolomide cytotoxicity increased linearly in Mawi with each subsequent dosing: from 1.4-fold (day 1) to 4.2-fold (day 5) with continuous 1 microM O(6)-BG. In contrast, no potentiation was observed in LS174T, a cell line that would appear to be 'tolerant' of methylation. Potentiation of BNCU cytotoxicity increased in both cell lines with repeat dosing, although the rate of increase was less than that observed with temozolomide and continuous 1 microM O(6)-BG in Mawi. These results suggest that repeat dosing of an AGT inhibitor and temozolomide may have a clinical role in the treatment of tumours that exhibit AGT-mediated resistance.

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“…Several interesting mechanistic details have been reported, however. It is known that mammalian mismatch repair systems use one DNA repair complex to repair A:C, T:T or T:C mismatches but have at least two separate repair complexes for G:T or G:U mispairs putatively arising from endogenous 5-methylcytosine or cytosine deamination events, respectively (7,8). One pathway to correct G:T mispairs appears confined primarily to CpG sequences in mammalian cells (7,8).…”

Section: Introductionmentioning

confidence: 99%

“…It is known that mammalian mismatch repair systems use one DNA repair complex to repair A:C, T:T or T:C mismatches but have at least two separate repair complexes for G:T or G:U mispairs putatively arising from endogenous 5-methylcytosine or cytosine deamination events, respectively (7,8). One pathway to correct G:T mispairs appears confined primarily to CpG sequences in mammalian cells (7,8). It is now evident that all combinations of mismatches can be repaired in mammalian cells; however, G:T mispairs are corrected with much higher efficiency than others (7,9).…”

Section: Introductionmentioning

confidence: 99%

Mammalian assay for site-specific DNA damage processing using the human H-rasproto-oncogene

Arcangeli

Williams

1995

Nucl Acids Res

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The human genomic H-ras proto-oncogene was inserted into an Epstein-Barr virus (EBV) vector (p220.2) that replicates synchronously with the cell cycle. Unique restriction enzyme sites, 30 bp apart, were created on either side of codon 12 to enable the construction of gapped heteroduplex (GHD) DNA. Depending upon experimental protocol, the gap could be located either on the coding (non-transcribed) strand or the non-coding (transcribed) strand. GHD DNA was created using a 1.8 kb segment of H-ras DNA containing exon 1, into which a synthetic 30 nucleotide oligomer containing a strand-and site-specific mismatched nucleotide was annealed. The 1.8 kb segment of H-ras DNA containing a codon 12; middle G:T, A:C or T:C mismatch has been religated with high efficiency into the EBV vector and transfected into NIH 3T3 cells using a mild liposome-mediated protocol. Subsequent hygromycin resistant NIH 3T3 colonies have been PCR amplified and sequenced. In this study, codon 12; middle nucleotide mismatch correction rates to wild-type G:C during replication in NIH 3T3 cells were 96.4% of G:T mismatches, 87.5% of A:C mismatches and 67% of T:C mismatches.

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DNA Mismatch Binding and Incision at Modified Guanine Bases by Extracts of Mammalian Cells: Implications for Tolerance to DNA Methylation Damage

Cited by 92 publications

References 38 publications

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

Potentiation of temozolomide and BCNU cytotoxicity by O6-benzylguanine: a comparative study in vitro

Mammalian assay for site-specific DNA damage processing using the human H-rasproto-oncogene

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