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

Sarek, G. and Kotsantis, P. and Ruis, P. and Van Ly, D. and Margalef, P. and Borel, V. and Zheng, X.-F. and Flynn, H.R. and Snijders, A.P. and Chowdhury, D. and Cesare, A.J. and Boulton, S.J. (2019) CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle. Nature, 575. pp. 523-527. ISSN 0028-0836

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.