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

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 and Simon J. Boulton ()
Additional contact information
Grzegorz Sarek: The Francis Crick Institute
Panagiotis Kotsantis: The Francis Crick Institute
Phil Ruis: The Francis Crick Institute
David Van Ly: University of Sydney
Pol Margalef: The Francis Crick Institute
Valerie Borel: The Francis Crick Institute
Xiao-Feng Zheng: Harvard Institute of Medicine
Helen R. Flynn: The Francis Crick Institute
Ambrosius P. Snijders: The Francis Crick Institute
Dipanjan Chowdhury: Harvard Institute of Medicine
Anthony J. Cesare: University of Sydney
Simon J. Boulton: The Francis Crick Institute

Nature, 2019, vol. 575, issue 7783, 523-527

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1744-8

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