英国弗朗西斯克里克研究所Simon J. Boulton团队，研究提出TRF2的CDK磷酸化在细胞周期中控制t-环动力学。这一研究成果2019年11月13日发表在国际学术期刊《自然》上。

他们在TRF2的Ser365的端粒蛋白复合体亚基中鉴定出CDK磷酸化位点，其PP6R3磷酸酶在S期去磷酸化提供了一个狭窄的窗口。在此期间RTEL1解旋酶可以瞬时进入并解开t环，以促进端粒复制。要从端粒释放RTEL1，需要对除S期外的TRF2的Ser365位点进行重新磷酸化。这不仅可以保护t环免受混杂的解绕和ATM的不适当激活，而且还可以消除端粒内和整个基因组DNA二级结构的复制冲突。因此，TRF2中的磷酸开关可协调细胞周期内t环的组装和拆卸，从而保护端粒免受复制压力和计划外的DNA损伤应答。

据悉，端粒蛋白复合体对端粒末端的保护可防止DNA损伤信号传导和染色体末端的混杂修复。有证据表明，端粒蛋白复合体可保护端粒末端，避免DNA损伤信号传导和染色体末端的混杂修复。3'单链端粒末端可以组装成套索状的t环构型，这已被提出是为了保护染色体末端不被识别为DNA双链断裂。还必须存在一种机制，以瞬时拆卸t环以允许精确的端粒复制并允许端粒酶进入3'末端以解决末端复制问题。然而，t环在端粒末端保护中的调控和生理学重要性仍然未知。

附：英文原文

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

Author: 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

Issue&Volume: 2019-11-13

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. A phospho-switch is identified in the shelterin subunit TRF2 that regulates transient recruitment of the RTEL1 helicase to, and release from, telomeres, and provides a narrow window during which RTEL1 can unwind t-loops to facilitate telomere replication.

DOI: 10.1038/s41586-019-1744-8

Source:https://www.nature.com/articles/s41586-019-1744-8