Phosphorylated (pT371)TRF1 is recruited to sites of DNA damage to facilitate homologous recombination and checkpoint activation.
Phosphorylated (pT371)TRF1 is recruited to sites of DNA damage to facilitate homologous recombination and checkpoint activation.
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DOI：
10.1093/nar/gkt775
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发表时间：
2013-12
影响因子：
14.9
通讯作者：
Zhu XD
中科院分区：
文献类型：
--
作者：
McKerlie M;Walker JR;Mitchell TR;Wilson FR;Zhu XD
TRF 1是端粒DNA结合蛋白，在端粒代谢中起重要作用。我们以前曾报道，一部分内源性TRF 1可以稳定存在的端粒染色质时，它是磷酸化的T371由Cdk 1，然而，这种端粒自由（pT 371）TRF 1的作用还没有得到充分的表征。在这里，我们表明，磷酸化（pT 371）TRF 1被招募到DNA损伤的网站，形成损伤诱导的病灶，电离辐射（IR），依托泊苷和喜树碱。我们发现IR诱导的（pT 371）TRF 1灶的形成依赖于ATM和Mre 11/Rad 50/Nbs 1介导的DNA损伤反应。虽然功能性BRCA 1的丧失损害了IR诱导的（pT 371）TRF 1灶的形成，但53 BP 1或Rif 1的缺失刺激了IR诱导的（pT 371）TRF 1灶的形成。此外，我们发现TRF 1缺失或T371磷酸化的缺乏会损害DNA末端切除和通过同源重组修复非端粒DNA双链断裂。T371处TRF 1磷酸化的缺乏也阻碍了G2/M检查点的激活，并使细胞对PARP抑制、IR和喜树碱敏感。总的来说，这些结果揭示了磷酸化（pT 371）TRF 1在促进DNA双链断裂修复和维持基因组完整性方面的一种新的但重要的功能。
TRF1, a duplex telomeric DNA-binding protein, plays an important role in telomere metabolism. We have previously reported that a fraction of endogenous TRF1 can stably exist free of telomere chromatin when it is phosphorylated at T371 by Cdk1; however, the role of this telomere-free (pT371)TRF1 has yet to be fully characterized. Here we show that phosphorylated (pT371)TRF1 is recruited to sites of DNA damage, forming damage-induced foci in response to ionizing radiation (IR), etoposide and camptothecin. We find that IR-induced (pT371)TRF1 foci formation is dependent on the ATM- and Mre11/Rad50/Nbs1-mediated DNA damage response. While loss of functional BRCA1 impairs the formation of IR-induced (pT371)TRF1 foci, depletion of either 53BP1 or Rif1 stimulates IR-induced (pT371)TRF1 foci formation. In addition, we show that TRF1 depletion or the lack of its phosphorylation at T371 impairs DNA end resection and repair of nontelomeric DNA double-strand breaks by homologous recombination. The lack of TRF1 phosphorylation at T371 also hampers the activation of the G2/M checkpoint and sensitizes cells to PARP inhibition, IR and camptothecin. Collectively, these results reveal a novel but important function of phosphorylated (pT371)TRF1 in facilitating DNA double-strand break repair and the maintenance of genome integrity.
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影响因子：
11.4
作者：
Bonetti, Diego;Anbalagan, Savani;Longhese, Maria Pia
通讯作者：
Longhese, Maria Pia
影响因子：
14.8
作者：
Dupre, Aude;Boyer-Chatenet, Louise;Gautier, Jean
通讯作者：
Gautier, Jean
影响因子：
30.8
作者：
Broccoli, D;Smogorzewska, A;deLange, T
通讯作者：
deLange, T
影响因子：
1.7
作者：
Iliakis, G;Wang, H;Pantelias, G
通讯作者：
Pantelias, G
由 53BP1-RIF1 和 BRCA1-CtIP 组成的细胞周期依赖性调节回路控制 DNA 修复途径的选择。
影响因子：
16
作者：
Escribano-Diaz, Cristina;Orthwein, Alexandre;Durocher, Daniel
通讯作者：
Durocher, Daniel