The end protection problem-an unexpected twist in the tail

Genes Dev. 2021 Jan 1;35(1-2):1-21. doi: 10.1101/gad.344044.120. Epub 2020 Dec 23.


In this perspective, we introduce shelterin and the mechanisms of ATM activation and NHEJ at telomeres, before discussing the following questions: How are t-loops proposed to protect chromosome ends and what is the evidence for this model? Can other models explain how TRF2 mediates end protection? Could t-loops be pathological structures? How is end protection achieved in pluripotent cells? What do the insights into telomere end protection in pluripotent cells mean for the t-loop model of end protection? Why might different cell states have evolved different mechanisms of end protection? Finally, we offer support for an updated t-loop model of end protection, suggesting that the data is supportive of a critical role for t-loops in protecting chromosome ends from NHEJ and ATM activation, but that other mechanisms are involved. Finally, we propose that t-loops are likely dynamic, rather than static, structures.

Keywords: DNA damage response; NHEJ; TRF2; pluripotency; somatic cells; t-loops; telomeres.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Chromosomal Instability
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair / physiology*
  • DNA Repair
  • Embryonic Stem Cells
  • Humans
  • Models, Biological
  • Pluripotent Stem Cells
  • Telomere / metabolism*
  • Telomere / pathology*
  • Telomeric Repeat Binding Protein 2 / metabolism


  • Telomeric Repeat Binding Protein 2
  • Ataxia Telangiectasia Mutated Proteins