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Aclarubicin Reduces the Nuclear Mobility of Human DNA Topoisomerase IIβ

Keiko Morotomi-Yano1, Ken-Ichi Yano1,2

  • 1Institute of Industrial Nanomaterials, Kumamoto University, Kumamoto 860-8555, Japan.

International Journal of Molecular Sciences
|October 16, 2024
PubMed

Insights

Aclarubicin, an anthracycline, unexpectedly reduces the nuclear mobility of DNA topoisomerase II beta (TOP2B), independent of its enzymatic activity. This finding reveals a novel cellular effect of aclarubicin on TOP2B.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • DNA topoisomerase II (TOP2) enzymes are crucial for resolving DNA topological issues during transcription and other nuclear processes.
  • Aclarubicin, an anthracycline, is known to inhibit TOP2 by preventing its association with DNA, affecting early catalytic steps.

Purpose of the Study:

  • To investigate the effect of aclarubicin on the subnuclear distribution and mobility of human TOP2B.
  • To elucidate the mechanism underlying aclarubicin's impact on TOP2B function in the cellular environment.

Main Methods:

  • Fluorescence Recovery After Photobleaching (FRAP) analysis to assess EGFP-tagged TOP2B nuclear mobility.
  • Utilized TOP2B mutants defective in ATPase or topoisomerase activity.
  • Immunofluorescence analysis to evaluate DNA damage induction by etoposide.

Main Results:

  • Aclarubicin significantly decreased the nuclear mobility of EGFP-tagged TOP2B in a concentration-dependent manner.
  • This reduction in mobility occurred independently of TOP2B's ATPase or topoisomerase enzymatic activities.
  • Aclarubicin was found to antagonize etoposide-induced DNA damage.

Conclusions:

  • Aclarubicin exhibits a previously unrecognized effect on TOP2B nuclear mobility within the cell.
  • The drug's impact on TOP2B mobility is distinct from its known inhibition of TOP2-DNA association.
  • These findings offer new insights into aclarubicin's cellular actions beyond its direct enzymatic inhibition.
Keywords:
DNA topoisomerase IITOP2 inhibitoraclarubicinlive cell imaging

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