Dif1 is a DNA-damage-regulated facilitator of nuclear import for ribonucleotide reductase.
Dif1 is a DNA-damage-regulated facilitator of nuclear import for ribonucleotide reductase.
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DOI：
10.1016/j.molcel.2008.08.018
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发表时间：
2008-10-10
期刊：
影响因子：
16
通讯作者：
Elledge, Stephen J.
中科院分区：
文献类型：
--
作者：
Lee, Yang David;Wang, Jun;Stubbe, JoAnne;Elledge, Stephen J.
dNTP浓度的控制对DNA合成和修复的保真度至关重要。调控的一个层面是通过核糖核苷酸还原酶的亚细胞定位。在葡萄球菌中，小亚基Rnr2-Rnr4是核基，而大亚基Rnr1是细胞质。在s期或dna损伤的反应中，Rnr2-Rnr4进入细胞质结合Rnr1，形成活性复合物。我们之前报道过Wtm1在细胞核中锚定Rnr2-Rnr4。在这里，我们发现了调控Rnr2-Rnr4定位的DIF1。Dif1通过保守的Hug结构域直接与Rnr2-Rnr4复合物结合，驱动核输入。Dif1同时受细胞周期和dna损伤调控，后者通过Mec1-Dun1途径调控。在DNA损伤的反应中，Dun1直接磷酸化Dif1使Dif1失活并降解，使Rnr2-Rnr4成为细胞质。我们提出Rnr2-Rnr4核定位是通过wtm1介导的核保留来限制出口，以及通过Dif1调节核进口的动态组合来实现的。
The control of dNTP concentrations is critical to the fidelity of DNA synthesis and repair. One level of regulation is through subcellular localization of ribonucleotide reductase. In S. cerevisiae, the small subunit, Rnr2-Rnr4, is nuclear while the large subunit, Rnr1, is cytoplasmic. In response to S-phase or DNA-damage, Rnr2-Rnr4 enters the cytoplasm to bind Rnr1, forming an active complex. We previously reported that Wtm1 anchors Rnr2-Rnr4 in the nucleus. Here, we identify DIF1 which regulates localization of Rnr2-Rnr4. Dif1 binds directly to the Rnr2-Rnr4 complex through a conserved Hug domain to drive nuclear import. Dif1 is both cell cycle- and DNA-damage regulated, the latter through the Mec1-Dun1 pathway. In response to DNA damage, Dun1 directly phosphorylates Dif1 to both inactivate and degrade Dif1, allowing Rnr2-Rnr4 to become cytoplasmic. We propose that Rnr2-Rnr4 nuclear localization is achieved by a dynamic combination of Wtm1-mediated nuclear retention to limit export, coupled with regulated nuclear import through Dif1.
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