Flap endonuclease 1 contributes to telomere stability
Flap endonuclease 1 contributes to telomere stability
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DOI：
10.1016/j.cub.2008.02.071
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发表时间：
2008-04-08
期刊：
影响因子：
9.2
通讯作者：
Stewart, Sheila A.
中科院分区：
文献类型：
--
作者：
Saharia, Abhishek;Guittat, Lionel;Stewart, Sheila A.
端粒稳定性在基因组稳定性的保存中起着重要作用，它是通过端粒特异性蛋白和DNA修复与复制蛋白的协调作用来维持的[1,2]。皮瓣内切酶1 （Flap endonuclease 1, FEN1）是一种参与滞后链DNA复制、碱基切除修复、同源重组和停滞复制叉重新启动的蛋白[3,4]。在这里，我们证明了FEN1的缺失导致端粒功能障碍，其特征是γ - H2AX的存在和姐妹端粒的丢失。催化活性端粒酶（一种将端粒重复序列添加到染色体末端的逆转录酶）的表达足以在FEN1缺失时挽救端粒功能障碍。引人注目的是，FEN1耗竭完全消除了由滞后链DNA复制复制的端粒。利用保留定位到端粒重复序列能力的FEN1突变蛋白进行的遗传拯救实验表明，FEN1的核酸酶活性以及与Werner蛋白（WRN）和端粒结合蛋白（TRF2）相互作用的能力是FEN1在端粒活性所必需的。考虑到FEN1在滞后链DNA复制和停滞复制叉的重新启动中的作用，我们提出FEN1通过确保端粒的有效复制来促进端粒的稳定性。
Telomere stability plays an important role in the preservation of genomic stability and is maintained through the coordinated actions of telomere-specific proteins and DNA repair and replication proteins [1, 2]. Flap endonuclease 1 (FEN1) is a protein that plays a role in lagging-strand DNA replication, base excision repair, homologous recombination, and reinitiation of stalled replication forks [3,4]. Here, we demonstrate that FEN1 depletion leads to telomere dysfunction characterized by the presence of gamma H2AX and sister telomere loss. Expression of catalytically active telomerase, the reverse transcriptase that adds telomeric repeats to chromosome ends, was sufficient to rescue telomere dysfunction upon FEN1 depletion. Strikingly, FEN1 depletion exclusively abrogates telomeres replicated by lagging-strand DNA replication. Genetic rescue experiments utilizing FEN1 mutant proteins that retained the ability to localize to telomeric repeats revealed that FEN1's nuclease activity and ability to interact with the Werner protein (WRN) and telomere-binding protein (TRF2) were required for FEN1 activity at the telomere. Given FEN1's role in lagging-strand DNA replication and reinitiation of stalled replication forks, we propose that FEN1 contributes to telomere stability by ensuring efficient telomere replication.