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Related Concept Videos

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...
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...
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...
Drugs that Destabilize Microtubules01:10

Drugs that Destabilize Microtubules

Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing...
Translesion DNA Polymerases02:10

Translesion DNA Polymerases

Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
DNA Helicases00:55

DNA Helicases

DNA unwinding helicase enzymes are a type of motor protein. Motor proteins can translocate along filaments or polymers using energy generated from ATP hydrolysis. Helicases are involved in all the important cellular processes where DNA unwinding is required, such as DNA replication, repair, recombination, and transcription. They are present in all living organisms, but vary in their structure, function, and mechanism of action. For example, in prokaryotes, DnaB helicase binds and translocates...

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Related Experiment Video

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Simple and Fast Rolling Circle Amplification-Based Detection of Topoisomerase 1 Activity in Crude Biological Samples
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Drugging topoisomerases: lessons and challenges.

Yves Pommier1

  • 1Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States. pommier@nih.gov

ACS Chemical Biology
|December 25, 2012
PubMed
Summary

Topoisomerase inhibitors are crucial anticancer and antibacterial drugs that function by trapping enzymes on DNA. This review explores their mechanisms, clinical uses, and future challenges for targeted drug development.

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Area of Science:

  • Enzymology
  • Pharmacology
  • Molecular Biology

Background:

  • Topoisomerases are essential enzymes regulating DNA topology during replication and transcription.
  • Topoisomerase inhibitors are vital anticancer and antibacterial therapeutics.
  • These drugs act as poisons, trapping enzymes on DNA rather than through classical inhibition.

Purpose of the Study:

  • To review the catalytic mechanisms of topoisomerase enzyme families.
  • To explain the principle of interfacial inhibition by topoisomerase-targeted drugs.
  • To discuss challenges and prospects for developing and utilizing topoisomerase inhibitors.

Main Methods:

  • Review of catalytic mechanisms of human and bacterial topoisomerases.
  • Analysis of the interfacial inhibition mechanism of topoisomerase poisons.
  • Exploration of drug delivery, biomarker, combination therapy, and inhibitor development.

Main Results:

  • Topoisomerase inhibitors kill cells by trapping enzymes on DNA, a principle applicable to other inhibitors like PARP inhibitors.
  • Challenges include targeted delivery, patient selection, and combination therapies with DNA repair inhibitors.
  • There is an unmet need for inhibitors targeting type IA topoisomerases.

Conclusions:

  • Understanding topoisomerase mechanisms and interfacial inhibition is key to drug development.
  • Targeted delivery, biomarkers, and rational combinations will enhance therapeutic efficacy.
  • Further research is needed to develop novel inhibitors, particularly for type IA enzymes.