Antagonistic roles for the ubiquitin ligase Asr1 and the ubiquitin-specific protease Ubp3 in subtelomeric gene silencing.
Antagonistic roles for the ubiquitin ligase Asr1 and the ubiquitin-specific protease Ubp3 in subtelomeric gene silencing.
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泛素连接酶 Asr1 和泛素特异性蛋白酶 Ubp3 在亚端粒基因沉默中的拮抗作用。
DOI：
10.1073/pnas.1518375113
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发表时间：
2016
影响因子：
11.1
通讯作者：
Tansey,WilliamP
中科院分区：
文献类型：
--
作者：
McCann,TylerS;Guo,Yan;McDonald,WHayes;Tansey,WilliamP
泛素以及泛素-蛋白酶体系统的组成部分在基因转录调控中具有广泛的作用。尽管有很多泛素如何控制转录调节因子和共调节因子活性的例子，但由泛素依赖性过程直接控制的转录机制核心组件的例子却很少。芽殖酵母蛋白 Asr1 是 RPC (RING、PHD、CBD) 泛素连接酶家族的典型成员，其特征是存在氨基末端 RING（非常有趣的新基因）和 PHD（植物同源结构域）指，以及一个羧基末端结构域，可直接结合 RNA 聚合酶 II (pol II) 的最大亚基 Rpb1，响应与转录起始相关的磷酸化事件。 Asr1 介导的 pol II 寡聚泛素化导致酶的两个核心亚基喷射，并与聚合酶功能的抑制相关。在这里，我们提供的证据表明，Asr1 介导的 pol II 泛素化是亚端粒基因转录沉默所必需的。我们发现 Asr1 与端粒近端染色质相关，Asr1 泛素连接酶活性的破坏（或 Rpb1 内泛素化位点的突变）会诱导沉默基因序列的转录。此外，我们报告 Asr1 与 Ubp3 去泛素化酶相关，并且 Asr1 和 Ubp3 在设置沉默基因的转录水平中发挥拮抗作用。我们认为，通过非蛋白水解泛素化控制 pol II 提供了一种通过亚端粒染色质处 pol II 活性的瞬时和可逆抑制来强制沉默的机制。
Ubiquitin, and components of the ubiquitin–proteasome system, feature extensively in the regulation of gene transcription. Although there are many examples of how ubiquitin controls the activity of transcriptional regulators and coregulators, there are few examples of core components of the transcriptional machinery that are directly controlled by ubiquitin-dependent processes. The budding yeast protein Asr1 is the prototypical member of the RPC (RING, PHD, CBD) family of ubiquitin-ligases, characterized by the presence of amino-terminal RING (really interesting new gene) and PHD (plant homeo domain) fingers and a carboxyl-terminal domain that directly binds the largest subunit of RNA polymerase II (pol II), Rpb1, in response to phosphorylation events tied to the initiation of transcription. Asr1-mediated oligo-ubiquitylation of pol II leads to ejection of two core subunits of the enzyme and is associated with inhibition of polymerase function. Here, we present evidence that Asr1-mediated ubiquitylation of pol II is required for silencing of subtelomeric gene transcription. We show that Asr1 associates with telomere-proximal chromatin and that disruption of the ubiquitin-ligase activity of Asr1—or mutation of ubiquitylation sites within Rpb1—induces transcription of silenced gene sequences. In addition, we report that Asr1 associates with the Ubp3 deubiquitylase and that Asr1 and Ubp3 play antagonistic roles in setting transcription levels from silenced genes. We suggest that control of pol II by nonproteolytic ubiquitylation provides a mechanism to enforce silencing by transient and reversible inhibition of pol II activity at subtelomeric chromatin.