DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata.

  title={DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata.},
  author={Yves Pommier and Glenda Kohlhagen and Christian Bailly and Michael J. Waring and A Mazumder and Kurt W. Kohn},
  volume={35 41},
Ecteinascidin 743 is one of several related marine alkaloids isolated from the Caribbean tunicate Ecteinascidia turbinata. It is remarkably active and potent in a variety of in vitro and in vivo systems and has been selected for development as an anticancer agent. The present study investigates the interactions of ecteinascidin 743 with DNA. Ecteinascidin 743 retarded the electrophoretic migration of both supercoiled and relaxed simian virus 40 DNA even in the presence of sodium dodecyl sulfate… Expand
The inefficiency of incisions of ecteinascidin 743-DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent.
The wedge-shaped Et 743, which forces open the minor groove of DNA, introducing a major groove bend, and the extrahelical protrusion of the C-subunit of Et 7 43 provide unique characteristics alongside the hydrogen-bonding stabilization of a covalent DNA adduct, which is proposed to be an intermediate in NER processing of Et 5'-NG(A/T) and 5'-PyGG. Expand
Poisoning of human DNA topoisomerase I by ecteinascidin 743, an anticancer drug that selectively alkylates DNA in the minor groove.
Data indicate that DNA minor groove alkylation by Et743 induces top1-mediated protein-linked DNA breaks and that top1 is a target for Et 743 in vitro and in vivo. Expand
A 3.(ET743)-DNA complex that both resembles an RNA-DNA hybrid and mimicks zinc finger-induced DNA structural distortions.
It is shown that head-to-tail binding of three ET743 molecules to three adjacent optimal binding sites stabilizes a DNA structure whose conformation is intermediate between A- and B-form DNA. Expand
DNA Structural Similarity in the 2:1 Complexes of the Antitumor Drugs Trabectedin (Yondelis) and Chromomycin A3 with an Oligonucleotide Sequence Containing Two Adjacent TGG Binding Sites on Opposing Strands
Simultaneous drug binding to the two strands in the manner described here is proposed to stabilize the helical structure of duplex DNA to prevent or hamper strand separation and stall replication and transcription forks. Expand
Ecteinascidin 743 induces protein-linked DNA breaks in human colon carcinoma HCT116 cells and is cytotoxic independently of topoisomerase I expression.
The sensitivity of camptothecin-resistant mouse leukemia P388/ CPT45 cells, which fail to express detectable top1, was similar to the sensitivity of wild-type P388 cells, suggesting that top1 is not a critical target for the antiproliferative activity of Et743. Expand
DNA sequence–selective adenine alkylation, mechanism of adduct repair, and in vivo antitumor activity of the novel achiral seco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145
Its novel structure and in vivo activity renders AS-I-145 a new paradigm in the design of novel achiral analogues of CC-1065 and the duocarmycins. Expand
Increased DNA binding specificity for antitumor ecteinascidin 743 through protein-DNA interactions?
By studying the complexes of ET743 with two DNA target sequences, it is shown that drug binding brings about widening of the minor groove and bending toward the major groove, and the minor grooves of DNA when bound to the zinc fingers of EGR-1 and in the covalent complex withET743 are virtually superimposable. Expand
Inhibition of RecBCD enzyme by antineoplastic DNA alkylating agents.
The results show that DNA alkylation does not significantly perturb the allosteric interaction that activates the enzyme for ATP hydrolysis, as the efficiency of ATP utilization for DNA unwinding is affected only marginally. Expand
The antitumor agent ecteinascidin 743: characterization of its covalent DNA adducts and chemical stability.
The results from this study demonstrate that Et 743 differs from other DNA alkylating agents by its effects on DNA structure and sequence-dependent chemical stability. Expand
Protein Recognition in Drug-Induced DNA Alkylation: When the Moonlight Protein GAPDH Meets S23906-1/DNA Minor Groove Adducts
The aim of this review is to highlight the variety of established protein recognition of DNA adducts to particularly focus on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) function in DNAAdduct interaction with illustration using original experiments performed with S23906-1/DNA adduct. Expand