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Related Concept Videos

Inhibitors of Bacterial DNA Synthesis01:28

Inhibitors of Bacterial DNA Synthesis

Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These antibiotics are selectively...
DNA Topoisomerases02:02

DNA Topoisomerases

Topoisomerases are enzymes that relax overwound DNA molecules during various cell processes, including DNA replication and transcription. These enzymes regulate positive and negative DNA supercoiling without changing the nucleotide sequence. DNA overwinding in a clockwise direction results in positively supercoiled DNA, whereas underwinding in a counterclockwise direction produces negatively supercoiled DNA.
Types and Mechanism of action
Topoisomerases are divided into two main types.  Type I...
Conservative Site-specific Recombination and Phase Variation02:53

Conservative Site-specific Recombination and Phase Variation

Because the DNA segments are cut and reorganized in a direction-specific manner, site-specific recombination has emerged as an efficient genetic engineering technique. Flippase and Cyclization recombinases or Flp and Cre, respectively, are two members of the tyrosine recombinase family derived from bacteriophages, that are used to mediate site-specific DNA insertions, deletions, and targeted expression of proteins in mammalian cell lines.
The recognition sites for Cre recombinase called LoxP...
DNA Base Pairing02:27

DNA Base Pairing

Erwin Chargaff’s rules on DNA equivalence paved the way for the discovery of base pairing in DNA. Chargaff’s rules state that in a double-stranded DNA molecule,
Single-Strand DNA Binding Proteins01:03

Single-Strand DNA Binding Proteins

For successful DNA replication, the unwinding of double-stranded DNA must be accompanied by stabilization and protection of the separated single strands of the DNA. This crucial task is performed by single-strand DNA-binding (SSB) proteins. They bind to the DNA in a sequence-independent manner, which means that the nitrogenous bases of the DNA need not be present in a specific order for binding of SSB proteins to it. The binding of SSB proteins straightens single-stranded DNA (ssDNA) and makes...
Inhibitors of Bacterial Protein Synthesis01:25

Inhibitors of Bacterial Protein Synthesis

Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...

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Simple and Fast Rolling Circle Amplification-Based Detection of Topoisomerase 1 Activity in Crude Biological Samples
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Sequence-specific base pair mimics are efficient topoisomerase IB inhibitors.

Pierre Vekhoff1, Maria Duca, Dominique Guianvarc'h

  • 1CNRS UMR7196, Muséum National d'Histoire Naturelle, 43 rue Cuvier, 75005 Paris, France.

Biochemistry
|November 30, 2011
PubMed
Summary

Novel DNA-targeting base pair mimics act as potent topoisomerase I inhibitors. By intercalating into DNA, these compounds stabilize the enzyme-DNA complex, offering a new strategy for antitumor drug development.

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Area of Science:

  • Molecular Biology
  • Medicinal Chemistry
  • Biochemistry

Background:

  • Topoisomerase I is crucial for DNA topology, targeted by antitumor drugs like camptothecin.
  • Camptothecin derivatives function as base pair mimics, intercalating into DNA within the enzyme-inhibitor complex.
  • Stabilizing the topoisomerase I-DNA cleavage complex inhibits DNA religation, a key mechanism for anticancer activity.

Purpose of the Study:

  • To investigate if base pair mimics can inhibit topoisomerase I religation.
  • To design and synthesize novel nucleobase analogues targeting specific DNA sequences.
  • To evaluate the inhibitory potential of these analogues on topoisomerase I activity.

Main Methods:

  • Synthesis of aminophenyl-thiazole nucleobase analogues.
  • Conjugation of analogues to triplex-forming oligonucleotides for sequence-specific DNA targeting.
  • Assays to measure topoisomerase I-mediated DNA cleavage and inhibition of religation.
  • Evaluation of compound activity with and without triplex formation.

Main Results:

  • Three synthesized nucleobase analogues demonstrated potent topoisomerase I inhibition when targeted to DNA.
  • Sequence-specific targeting via triplex-forming oligonucleotides was essential for potent inhibition.
  • The intercalation of the nucleobase analogue into the DNA upon triplex formation was identified as the key inhibitory feature.
  • Weak DNA binding and cleavage were observed in the absence of triplex formation.

Conclusions:

  • Sequence-specific targeting of base pair mimics to DNA enables potent topoisomerase I inhibition.
  • Intercalation of the nucleobase analogue within the DNA is critical for stabilizing the cleavage complex.
  • This approach offers a promising new avenue for developing novel anticancer therapeutics targeting topoisomerase I.