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Telomeres avoid end detection by severing the checkpoint signal transduction pathway

Tiago Carneiro1, Lyne Khair, Clara C Reis

  • 1Instituto Gulbenkian de Ciência, Oeiras 2781-901, Portugal.

Nature
|September 11, 2010
PubMed

Insights

Telomeres prevent cell cycle arrest by lacking specific epigenetic markers like H4K20me2, despite recruiting DNA repair proteins. This chromatin privilege ensures proper chromosome end protection without triggering DNA damage responses.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Epigenetics

Background:

  • Telomeres protect chromosome ends from DNA damage recognition.
  • Proteins involved in DNA repair and checkpoints are recruited to telomeres, yet permanent cell cycle arrest is avoided.
  • The mechanism preventing telomeres from activating DNA damage responses remains unclear.

Purpose of the Study:

  • To investigate how telomeres prevent DNA damage responses from causing cell cycle arrest in fission yeast.
  • To identify the molecular mechanisms underlying telomere-specific chromatin regulation.
  • To understand the role of epigenetic modifications in telomere function.

Main Methods:

  • Analysis of fission yeast (Schizosaccharomyces pombe) mutants lacking Taz1 (an orthologue of human TRF1/TRF2).
  • Recruitment of DNA repair proteins (Rad22/RAD52, Rhp51/RAD51) and checkpoint sensors (RPA, Rad9, Rad26/ATRIP, Cut5/Rad4/TOPBP1) to telomeres was assessed.
  • Investigated the role of histone modifications (H4K20me2, γH2A) and telomere-binding proteins (Pot1, Ccq1) in checkpoint activation.

Main Results:

  • Cells lacking Taz1 recruited DNA repair and checkpoint proteins to telomeres but failed to accumulate Crb2 (53BP1), thus not activating Chk1-dependent cell cycle arrest.
  • Artificial recruitment of Crb2 (53BP1) to taz1Δ telomeres induced a full checkpoint response and cell cycle arrest.
  • Telomeres lack H4K20me2, a modification required for stable Crb2 (53BP1) association, unlike internal chromosome regions.
  • Loss of Pot1 or Ccq1 from telomeres led to Crb2 (53BP1) foci, Chk1 activation, and cell cycle arrest.
  • Telomeres are chromatin-privileged regions lacking essential epigenetic markers for DNA damage response amplification.

Conclusions:

  • Fission yeast telomeres are epigenetically distinct, lacking H4K20me2, which prevents amplification of DNA damage signals.
  • Exclusion of Crb2 (53BP1) from telomeres, mediated by Pot1 and Ccq1, is crucial for preventing cell cycle arrest.
  • This chromatin privilege ensures telomere maintenance and function by preventing inappropriate checkpoint activation, which is vital for recruiting telomerase via ATM/ATR kinases.

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