Laboratory of Cell Biology and Genetics, The Rockefeller University, New York, NY 10065, USA.
J Cell Biol. 2009 Nov 2;187(3):385-98. doi: 10.1083/jcb.200902039.
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.
Rif1，最初在芽殖酵母中因其在端粒上的作用而被识别，已被牵连到哺乳动物中的各种细胞过程中，包括干细胞的多能性、对双链断裂的反应和乳腺癌的发展。由于 Rif1 的分子功能尚不清楚，我们检查了 Rif1 缺乏对小鼠细胞的影响。 Rif1 缺乏会导致胚胎发育失败，并且从小鼠胚胎成纤维细胞中条件性删除 Rif1 会影响 S 期进展，使细胞对复制毒物高度敏感。 Rif1 缺乏不会改变 DNA 复制检查点的激活，而是会影响修复的执行。针对人 Rif1 的 RNA 干扰会降低同源定向修复 (HDR) 的效率，并且 Rif1 缺乏会导致 HDR 因子 Rad51 的异常聚集。与 S 期进展的作用一致，Rif1 在停滞的复制叉处积累，优先围绕着着丝粒异染色质。总的来说，这些发现揭示了 Rif1 在通过促进 HDR 修复停滞复制叉方面的功能。
