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Related Concept Videos

DNA Topoisomerases02:02

DNA Topoisomerases

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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.
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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...
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Microtubules are dynamic structures that undergo cycles of catastrophe and rescue. The microtubules play a central role in cell division by forming the spindle apparatus for segregating the chromosomes. This makes them ideal targets for regulating dividing cells in tumors and malignant cancer cells. Microtubule stabilizing drugs help stabilize the microtubule formation and promote its polymerization. Paclitaxel was the first microtubule stabilizing agent used as anticancer drug in chemotherapy...
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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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The destabilization of microtubules can occur during different stages of the microtubule lifecycle, such as nucleation or elongation. It can take place at either end of the microtubule or in the microtubule lattices as a whole. The lifespan of individual microtubules within a cell varies according to the cell type and stage of the cell cycle. During interphase, the lifespan of the microtubule is about 30 minutes, while during cell division, it is about 15 minutes. In axonal microtubules of...
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Simple and Fast Rolling Circle Amplification-Based Detection of Topoisomerase 1 Activity in Crude Biological Samples
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YM155 inhibits topoisomerase function.

Mei Hong1, Ming-Qiang Ren, Jeane Silva

  • 1aCancer Center, Georgia Regents University Cancer Center bDepartment of Surgery cDepartment of ENT Surgery, Center for Biotechnology and Genomic Medicine dDepartment of Medicine, Medical College of Georgia, Augusta eDepartment of Chemistry, Georgia State University, Atlanta, Georgia, USA.

Anti-Cancer Drugs
|October 19, 2016
PubMed
Summary
This summary is machine-generated.

YM155 (sepantronium bromide) inhibits DNA topoisomerase activity, impacting cell cycle progression and DNA repair. This clarifies its mechanism, crucial for developing YM155 as a cancer therapeutic.

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Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • YM155 (sepantronium bromide) is a survivin suppressant evaluated in clinical trials.
  • Despite early promise, later clinical studies of YM155 yielded negative results.
  • Understanding YM155's precise mechanism of action is critical for its therapeutic development.

Purpose of the Study:

  • To elucidate the mechanism of action of YM155.
  • To investigate YM155's interaction with DNA and its effect on DNA-related enzymes.
  • To determine if YM155 functions as a DNA intercalator.

Main Methods:

  • Viscosity, circular dichroism, and absorption spectroscopy were used to assess DNA interaction.
  • Molecular modeling was employed to rule out DNA intercalation.
  • Inhibition of topoisomerase 2α decatenation and topoisomerase 1-mediated DNA cleavage was measured.
  • Effects on DNA double-strand break repair were assessed.

Main Results:

  • YM155 did not exhibit characteristics of a typical DNA intercalator.
  • Molecular modeling excluded YM155-induced DNA intercalation.
  • YM155 was found to inhibit the enzymatic function of topoisomerase 2α and topoisomerase 1.
  • YM155 treatment resulted in the inhibition of DNA double-strand break repair.
  • YM155 induced cell cycle arrest at the G1/S phase and impaired mitotic progression.

Conclusions:

  • YM155's mechanism of action involves the inhibition of topoisomerase enzymes, not DNA intercalation.
  • Inhibition of topoisomerases by YM155 leads to impaired DNA repair and cell cycle disruption.
  • These findings provide a clearer understanding of YM155's effects, guiding future therapeutic strategies.