Mammalian Rif1 contributes to replication stress survival and homology-directed repair.
Mammalian Rif1 contributes to replication stress survival and homology-directed repair.
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DOI：
10.1083/jcb.200902039
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发表时间：
2009-11-02
期刊：
影响因子：
--
通讯作者：
de Lange T
中科院分区：
文献类型：
--
作者：
Buonomo SB;Wu Y;Ferguson D;de Lange T
在S阶段，多功能蛋白Rif1在停滞的复制叉处积累，以促进DNA修复。Rif1最初被认为是在发芽酵母的端粒上发挥作用，现在已经被认为与哺乳动物的多种细胞过程有关，包括干细胞的多能性，对双链断裂的反应，以及乳腺癌的发生。由于Rif1的分子功能尚不清楚，我们研究了Rif1缺陷在小鼠细胞中的后果。Rif1缺乏会导致胚胎发育失败，而小鼠胚胎成纤维细胞Rif1的条件缺失会影响S期的进展，使细胞对复制毒物高度敏感。Rif1缺陷不会改变DNA复制检查点的激活，但会影响修复的执行。对人Rif1的RNA干扰降低了同源定向修复(HDR)的效率，而Rif1缺乏会导致HDR因子RAD51的异常聚集。与S期进展相一致的是，Rif1聚集在停滞的复制叉处，优先聚集在着丝粒周围的异染色质周围。总而言之，这些发现揭示了Rif1通过促进HDR在修复停滞的叉子中的功能。
Multifunctional protein Rif1 accumulates at stalled replication forks to facilitate DNA repair during S phase. Rif1, originally recognized for its role at telomeres in budding yeast, has been implicated in a wide variety of cellular processes in mammals, including pluripotency of stem cells, response to double-strand breaks, and breast cancer development. As the molecular function of Rif1 is not known, we examined the consequences of Rif1 deficiency in mouse cells. Rif1 deficiency leads to failure in embryonic development, and conditional deletion of Rif1 from mouse embryo fibroblasts affects S-phase progression, rendering cells hypersensitive to replication poisons. Rif1 deficiency does not alter the activation of the DNA replication checkpoint but rather affects the execution of repair. RNA interference to human Rif1 decreases the efficiency of homology-directed repair (HDR), and Rif1 deficiency results in aberrant aggregates of the HDR factor Rad51. Consistent with a role in S-phase progression, Rif1 accumulates at stalled replication forks, preferentially around pericentromeric heterochromatin. Collectively, these findings reveal a function for Rif1 in the repair of stalled forks by facilitating HDR.
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影响因子：
64.5
作者：
Casper, AM;Nghiem, P;Glover, TW
通讯作者：
Glover, TW
影响因子：
10.5
作者：
Bugreev, Dmitry V.;Yu, Xiong;Mazin, Alexander V.
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影响因子：
2.5
作者：
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DOI：
10.1073/pnas.1633296100
发表时间：
2003-08-19
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
64.5
作者：
Barlow, C;Hirotsune, S;WynshawBoris, A
通讯作者：
WynshawBoris, A