CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle

Nature. 2019 Nov;575(7783):523-527. doi: 10.1038/s41586-019-1744-8. Epub 2019 Nov 13.


The protection of telomere ends by the shelterin complex prevents DNA damage signalling and promiscuous repair at chromosome ends. Evidence suggests that the 3' single-stranded telomere end can assemble into a lasso-like t-loop configuration1,2, which has been proposed to safeguard chromosome ends from being recognized as DNA double-strand breaks2. Mechanisms must also exist to transiently disassemble t-loops to allow accurate telomere replication and to permit telomerase access to the 3' end to solve the end-replication problem. However, the regulation and physiological importance of t-loops in the protection of telomere ends remains unknown. Here we identify a CDK phosphorylation site in the shelterin subunit at Ser365 of TRF2, whose dephosphorylation in S phase by the PP6R3 phosphatase provides a narrow window during which the RTEL1 helicase can transiently access and unwind t-loops to facilitate telomere replication. Re-phosphorylation of TRF2 at Ser365 outside of S phase is required to release RTEL1 from telomeres, which not only protects t-loops from promiscuous unwinding and inappropriate activation of ATM, but also counteracts replication conflicts at DNA secondary structures that arise within telomeres and across the genome. Hence, a phospho-switch in TRF2 coordinates the assembly and disassembly of t-loops during the cell cycle, which protects telomeres from replication stress and an unscheduled DNA damage response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Cycle*
  • Cyclin-Dependent Kinases / metabolism*
  • DNA / biosynthesis
  • DNA / chemistry
  • DNA / metabolism
  • DNA Breaks, Double-Stranded
  • DNA Damage
  • DNA Helicases / metabolism
  • DNA Repair
  • DNA Replication
  • Fibroblasts
  • Genome / genetics
  • HEK293 Cells
  • Humans
  • Mice
  • Mutation
  • Phenotype
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • Phosphoserine / metabolism*
  • Proliferating Cell Nuclear Antigen / metabolism
  • S Phase
  • Shelterin Complex
  • Telomerase / metabolism
  • Telomere / genetics
  • Telomere / metabolism*
  • Telomere-Binding Proteins / chemistry
  • Telomere-Binding Proteins / metabolism
  • Telomeric Repeat Binding Protein 2 / chemistry*
  • Telomeric Repeat Binding Protein 2 / genetics
  • Telomeric Repeat Binding Protein 2 / metabolism*


  • Proliferating Cell Nuclear Antigen
  • Shelterin Complex
  • TERF2 protein, human
  • Telomere-Binding Proteins
  • Telomeric Repeat Binding Protein 2
  • Phosphoserine
  • DNA
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Cyclin-Dependent Kinases
  • Telomerase
  • Phosphoric Monoester Hydrolases
  • RTEL1 protein, human
  • DNA Helicases