Structure and mechanism of DNA topoisomerase II

Berger, James M.; Gamblin, S.J.; Harrison, Stephen C.; Wang, James C.

doi:10.1038/379225a0

Cited by 801 publications

(725 citation statements)

References 36 publications

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“…Topoisomerase I covalently binds to double-stranded DNA and induces transient single strand breaks to allow passage of one strand, 23 whereas topoisomerase II induces transient double strand breaks to allow passage of both strands. 24 Resistance to topoisomerase poisons has been mainly attributed to mutations in topoisomerase genes, to enhanced repair, and to overexpression of P-glycoprotein (Pgp), multidrug resistance protein (MRP), and breast cancer resistance protein (BCRP). 25,26 In addition, loss of MLH1 activity has also been reported to be associated with resistance to the topoisomerase II poisons doxorubicin and etoposide, 9,15 suggesting a role of mismatch repair in topoisomerase II poison-mediated cell killing.…”

Section: Discussionmentioning

confidence: 99%

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%

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

et al. 2001

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“…A priori, whether a positive or a negative node will be inverted by an intramolecular event of segment transport is expected to depend on two factors: the conformation of the DNA and the three-dimensional structure of the topoisomerase-DNA complex. Recent work on the three dimensional structure of a 92-kDa fragment of yeast DNA topoisomerase II has provided a detailed model of the complex between the enzyme and a G-segment (Berger et al 1996), but no information is available on the relative orientation of a pair of segments prior to segment crossing. Figure 5 depicts an arbitrary pair of contiguous G-and Tsegments forming either a negative or a positive node.…”

Section: Probability Of Yeast Dna Topoisomerase Ii-mediated Unlinkingmentioning

confidence: 99%

“…Recent biochemical (Roca & Wang 1992Roca et al 1993Lindsley & Wang 1993) and structural (Berger et al 1996) studies of yeast DNA topoisomerase II have provided substantial evidence in favour of an ATP-modulated protein-clamp model (Roca & Wang 1992. In this model, a free or DNA-bound enzyme is assumed to have two major conformations: a closed-clamp form when ATP or its nonhydrolysable b , -imido analogue AMPPNP is bound to the enzyme, and an open-clamp form in the absence of bound nucleotide.…”

Section: Introductionmentioning

confidence: 99%

The probabilities of supercoil removal and decatenation by yeast DNA topoisomerase II

Roca

Wang

1996

Genes to Cells

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Background: In yeast a single type II DNA topoisomerase is involved in both the removal of DNA supercoils and the unlinking of intertwined pairs of newly replicated chromosomes or plasmids; in bacteria, two type II enzymes, DNA gyrase and DNA topoisomerase IV, function separately in the passage of DNA segments in cis and in trans. To deduce the molecular characteristics of these enzyme-mediated reactions, the efficiencies of supercoil removal and decatenation by the yeast enzyme upon the addition of a nonhydrolysable ATP analogue were determined.

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“…Topoisomerase IIa (Topo IIa) is a vital nuclear DNA-binding enzyme that controls and modifies the topologic states of DNA (Berger et al, 1996) by combining nuclease, helicase and ligase activities. Topo IIa reduces DNA supercoiling and twisting by creating a double-strand nick that enables the passage of a second DNA double-strand through the break and subsequent religation of the cleaved DNA strand.…”

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confidence: 99%

DNA topoisomerase IIα expression and the response to primary chemotherapy in breast cancer

MacGrogan

Rudolph²,

Mascarel

et al. 2003

Br J Cancer

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The a isoform of Topoisomerase IIa (Topo IIa) is a proliferation marker as well as a target for several chemotherapeutic agents such as anthracyclines. In vitro studies have demonstrated the relationship between the Topo IIa expression level and chemosensitivity of target cancer cells. To verify this effect in vivo, we selected 125 patients presenting with T 2 43 cm and T 3 N 0 -1 M 0 breast tumours who were treated by six cycles of primary chemotherapy, including epirubicin before any surgery. Therapy response was assessed by clinical and X-ray mammogram measurements of tumour shrinkage. The pretherapeutic core biopsies were immunostained with a monoclonal antibody (Ki-S7) against Topo IIa. Ki-S7 positivity ranged from 0 to 50% (median, 15%). A high percentage of Ki-S7-positive cells (415%) was associated with tumour regression under chemotherapy (OR ¼ 2.88, CI: 1.3 -6.4, P ¼ 0.004). Ki-S7 further emerged as an independent predictor of tumour regression (OR ¼ 3.34, CI: 1.41 -7.93, P ¼ 0.006), together with tumour size of less than 40 mm (OR ¼ 3.82, CI: 1.58 -9.25, P ¼ 0.002) and negative oestrogen receptor (ER) status (OR ¼ 3.35, CI: 1.43 -7.86, P ¼ 0.005), in a multivariate analysis including tumour size, SBR grade, ER and PR status, Ki-67, p53 and Her-2/neu. Our clinical results confirm in vitro data on the relationship between Topo IIa expression and tumour chemosensitivity and thus may have important practical implications.

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Structure and mechanism of DNA topoisomerase II

Cited by 801 publications

References 36 publications

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

The probabilities of supercoil removal and decatenation by yeast DNA topoisomerase II

DNA topoisomerase IIα expression and the response to primary chemotherapy in breast cancer

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