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Cell cycle-dependent DNA damage signaling induced by ICRF-193 involves ATM, ATR, CHK2, and BRCA1

Iha Park1, Hava Karsenty Avraham

  • 1Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 4 Blackfan Circle, 3rd Floor, Boston, MA 02115, USA.

Experimental Cell Research
|April 25, 2006
PubMed

Insights

ICRF-193, a topoisomerase II inhibitor, triggers DNA damage signaling and cell cycle arrest. This DNA damage response is cell cycle-dependent, highlighting topoisomerase II

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Topoisomerase II is crucial for cell proliferation and survival.
  • It is a validated target for anticancer drug development.
  • ICRF-193 is a known catalytic inhibitor used to study topoisomerase II function.

Purpose of the Study:

  • To investigate the effects of ICRF-193 on DNA damage signaling.
  • To determine the cell cycle dependency of ICRF-193-induced DNA damage.
  • To elucidate the signaling pathways involved in the response to ICRF-193.

Main Methods:

  • Treatment of cells with ICRF-193.
  • Analysis of DNA damage markers (gamma-H2AX, 53BP1, NBS1, BRCA1, MDC1, FANCD2 foci, comet assay).
  • Cell cycle analysis and assessment of signaling pathway activation (ATM, ATR, CHK2, BRCA1 phosphorylation).

Main Results:

  • ICRF-193 treatment induced G2 arrest and significant DNA damage signaling.
  • Formation of multiple DNA damage foci (gamma-H2AX, 53BP1, NBS1, BRCA1, MDC1, FANCD2) and increased comet tail moment confirmed DNA damage.
  • ATM and ATR mediated the DNA damage signaling, which was cell cycle-dependent (S, G2, M, early/late G1 phases).

Conclusions:

  • ICRF-193 induces DNA damage signaling in a cell cycle-dependent manner.
  • Topoisomerase II activity is essential for cell cycle progression, including DNA decondensation.
  • These findings provide insights into the mechanism of action of topoisomerase II inhibitors.

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