Details

Autor(en) / Beteiligte

• Sarek, Grzegorz
• Kotsantis, Panagiotis
• Ruis, Phil
• Van Ly, David
• Margalef, Pol
• Borel, Valerie
• Zheng, Xiao-Feng
• Flynn, Helen R
• Snijders, Ambrosius P
• Chowdhury, Dipanjan
• Cesare, Anthony J
• Boulton, Simon J

Titel

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

Ist Teil von

• Nature (London), 2019-11, Vol.575 (7783), p.523-527

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 configuration , which has been proposed to safeguard chromosome ends from being recognized as DNA double-strand breaks . 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.