Phosphorylation of shelterin component TRF2 modulates telomere accessibility across the cell cycle.

  • Major Finding: Phosphorylation of shelterin component TRF2 modulates telomere accessibility across the cell cycle.

  • Mechanism: Phospho-dead TRF2 sequesters helicase RTEL1 and causes promiscuous t-loop unwinding.

  • Impact: This study provides a mechanistic basis for understanding how telomere length is maintained.


Maintenance of telomere length upon repeated cell divisions is essential for cancer cells. In cells, the single-stranded 3′ end of the telomere is suspected to form a lariat structure known as a t-loop, which may protect chromosome ends from being aberrantly targeted for DNA repair; however, this structure must be capable of disassembling to allow telomere replication during S phase. In an investigation of TRF2, a subunit of the telomere-protecting complex shelterin, Sarek, Kotsantis, and colleagues found that S-to-A mutations at a putative CDK phosphorylation site that generate a phospho-dead TRF2 cause telomere fragility. Additionally, S-to-D or S-to-E (phosphomimetic) mutations at the same site in TRF2 increased telomere loss and resulted in an abundance of extrachromosomal telomere circles. The phenotypes of cells with phospho-dead or phosphomimetic TRF2 mimic those those of cells defective in their ability to recruit the RTEL1 helicase to replication forks or telomeres, respectively. Accordingly, further experiments with the phosphomimetic mutants suggested that phosphorylation at this site (S365 in humans or S367 in mice) is a negative regulator of TRF2–RTEL1 interactions, causing telomere loss and increasing telomere circles. In contrast, interactions between the phospho-dead TRF2 mutant and RTEL1 were enhanced, causing telomere fragility. Mechanistically, it appeared that the phospho-dead TRF2 mutant's increased binding to RTEL1 may sequester the latter protein at telomeres, preventing its interactions with the essential processivity factor proliferating cell nuclear antigen and thus creating replicative stress. Experiments using super-resolution microscopy suggested that this RTEL1 sequestration caused promiscuous t-loop unwinding and diminished the number of t-loops. This unwinding generated linear telomeres, which triggered an ATM-dependent DNA-damage response, providing evidence that t-loops play an important role in blocking deleterious ATM activation at telomere ends. Collectively, these findings elucidate the existence of a TRF2 phosphoswitch underlying the transient binding and unbinding of RTEL1 to telomeres, mediating the transient disassembly of t-loops during S phase to allow telomere replication as well as making promiscuous t-loop unwinding outside S phase less likely.

Sarek G, Kotsantis P, Ruis P, Van Ly D, Margalef P, Borel V, et al. CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle. Nature 2019;575:523–7.

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