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A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest

Makoto T Hayashi1, Anthony J Cesare, James A J Fitzpatrick

  • 1The Salk Institute for Biological Studies, Molecular and Cellular Biology Department, La Jolla, California, USA.

Nature Structural & Molecular Biology
|March 13, 2012
PubMed

Insights

Prolonged mitotic arrest triggers telomere damage signals in human cells. This telomere deprotection, linked to cell cycle control, can be prevented by TRF2 or Aurora B kinase inhibition.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Telomere shortening and component disruption are known causes of telomere deprotection.
  • Telomeres are crucial for maintaining genomic stability and preventing chromosome fusions.

Purpose of the Study:

  • To investigate a novel pathway of telomere deprotection induced by prolonged mitotic arrest.
  • To elucidate the molecular mechanisms underlying mitotic telomere damage and its consequences.

Main Methods:

  • Human cells were subjected to prolonged mitotic arrest using various inhibitors (microtubule, kinesin, proteasome).
  • Telomere damage foci, TRF2 localization, telomeric overhangs, and ATM activation were assessed.
  • The roles of TRF2 and Aurora B kinase in mitotic telomere deprotection were evaluated.

Main Results:

  • Prolonged mitotic arrest induced damage signals specifically at telomeres.
  • Mitotic telomere deprotection involved TRF2 dissociation, 3'-overhang degradation, and ATM activation.
  • TRF2 overexpression or Aurora B kinase inhibition suppressed this deprotection.
  • p53-deficient cells escaping mitotic arrest became aneuploid, unlike normal cells.

Conclusions:

  • A novel pathway links prolonged mitotic arrest to telomere deprotection in human cells.
  • This suggests a telomere-dependent system monitors mitotic duration and progression.
  • Dysregulation of this system, particularly in p53-deficient cells, can lead to aneuploidy.

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