Rif1: A Conserved Regulator of DNA Replication and Repair Hijacked by Telomeres in Yeasts.
Rif1: A Conserved Regulator of DNA Replication and Repair Hijacked by Telomeres in Yeasts.
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DOI：
10.3389/fgene.2016.00045
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发表时间：
2016
影响因子：
3.7
通讯作者：
Shore D
中科院分区：
文献类型：
--
作者：
Mattarocci S;Hafner L;Lezaja A;Shyian M;Shore D
Rap 1相互作用因子1（Rif 1）最初在芽殖酵母酿酒酵母中被鉴定为端粒结合蛋白，其负调节端粒聚合酶介导的端粒延伸。虽然这种功能在远亲裂殖酵母裂殖酵母中是保守的，但最近的研究，无论是在酵母还是在后生动物中，都揭示了Rif 1在DNA复制和DNA修复的时间控制方面也具有更广泛的功能。Rif 1蛋白是大的，其特征是N-末端HEAT重复，预测形成一个细长的α-螺旋结构。此外，所有Rif 1同源物都含有两个短基序，缩写为RIFIF/SILK，其涉及PP 1（酵母Glc 7）磷酸酶的募集。在酵母中，已显示RIF/SILK结构域在控制DNA复制起始中起作用，至少部分通过复制前复合物中蛋白质的靶向去磷酸化。在人类细胞中，Rif 1通过与53 BP 1的相互作用被募集到DNA双链断裂处，在那里它抵消DNA切除，从而通过非同源末端连接促进修复。该功能需要N-末端含HEAT重复序列的结构域。有趣的是，该结构域也涉及酵母中未加帽端粒的DNA末端保护。最后，我们讨论部署在端粒的RIF 1在酵母从进化的角度来看，并在其最近发现的全球功能。
Rap1-interacting factor 1 (Rif1) was originally identified in the budding yeast Saccharomyces cerevisiae as a telomere-binding protein that negatively regulates telomerase-mediated telomere elongation. Although this function is conserved in the distantly related fission yeast Schizosaccharomyces pombe, recent studies, both in yeasts and in metazoans, reveal that Rif1 also functions more globally, both in the temporal control of DNA replication and in DNA repair. Rif1 proteins are large and characterized by N-terminal HEAT repeats, predicted to form an elongated alpha-helical structure. In addition, all Rif1 homologs contain two short motifs, abbreviated RVxF/SILK, that are implicated in recruitment of the PP1 (yeast Glc7) phosphatase. In yeasts the RVxF/SILK domains have been shown to play a role in control of DNA replication initiation, at least in part through targeted de-phosphorylation of proteins in the pre-Replication Complex. In human cells Rif1 is recruited to DNA double-strand breaks through an interaction with 53BP1 where it counteracts DNA resection, thus promoting repair by non-homologous end-joining. This function requires the N-terminal HEAT repeat-containing domain. Interestingly, this domain is also implicated in DNA end protection at un-capped telomeres in yeast. We conclude by discussing the deployment of Rif1 at telomeres in yeasts from both an evolutionary perspective and in light of its recently discovered global functions.