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The human decatenation checkpoint.

P B Deming1, C A Cistulli, H Zhao

  • 1Department of Pathology and Laboratory Medicine and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 11, 2001
PubMed
Summary
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The study reveals that ATR and BRCA1 proteins are crucial for the G2 checkpoint, preventing cell division until chromatid decatenation is complete. This ensures genetic stability by monitoring chromosome segregation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Chromatid catenation requires active monitoring in human cells.
  • Failure in decatenation triggers cell cycle arrest, preventing mitosis.
  • Topoisomerase II inhibitors like ICRF-193 block decatenation without causing DNA breaks.

Purpose of the Study:

  • To investigate the roles of ATR and BRCA1 in the G2 checkpoint response to decatenation failure.
  • To elucidate the molecular mechanisms underlying ICRF-193-induced mitotic delay.

Main Methods:

  • Treatment of normal and checkpoint-deficient human cells (A-T, BRCA1-mutant) with ICRF-193.
  • Quantification of mitotic delay.
  • Analysis of checkpoint protein phosphorylation and kinase activity.

Related Experiment Videos

  • Assessment of cyclin B1 localization and Cdk1 activity.
  • Evaluation of chromosomal aberrations in ATR(ki) cells.

    • Main Results:

    • A-T cells showed normal mitotic delay, indicating checkpoint-deficiency did not affect this response.
    • Mitotic delay was abolished in ATR kinase-inactive (ATR(ki)) cells and BRCA1-mutant cells.
    • BRCA1 restoration corrected the defect in HCC1937 cells.
    • No significant phosphorylation of hCds1/Chk1 or Cdk1 inhibition was observed.
    • Overexpression of nuclear cyclin B1 or inhibition of nuclear export reversed the delay.
    • ATR(ki) induction led to a 10-fold increase in chromosomal aberrations.

    Conclusions:

    • ATR and BRCA1 are essential components of the G2 checkpoint that enforces chromatid decatenation.
    • This checkpoint may function by excluding cyclin B1/Cdk1 complexes from the nucleus.
    • ATR plays a vital role in maintaining genetic stability.