The Francis Crick Institute
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CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle.

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journal contribution
posted on 2020-01-17, 16:58 authored by Grzegorz Sarek, Panagiotis Kotsantis, Phil Ruis, David Van Ly, Pol Margalef, Valerie Borel, Xiao-Feng Zheng, Helen R Flynn, Ambrosius P Snijders, Dipanjan Chowdhury, Anthony J Cesare, Simon J Boulton
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.


Crick (Grant ID: 10048, Grant title: Boulton FC001048) European Research Council (Grant ID: 742437 - TelMetab, Grant title: ERC 742437 - TelMetab)