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The ribonucleotide reductase inhibitor, Sml1, is sequentially phosphorylated, ubiquitylated and degraded in response to DNA damage

机译：核糖核苷酸还原酶抑制剂Sml1被磷酸化，泛素化并响应DNA损伤而降解

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摘要

Regulation of ribonucleotide reductase (RNR) is important for cell survival and genome integrity in the face of genotoxic stress. The Mec1/Rad53/Dun1 DNA damage response kinase cascade exhibits multifaceted controls over RNR activity including the regulation of the RNR inhibitor, Sml1. After DNA damage, Sml1 is degraded leading to the up-regulation of dNTP pools by RNR. Here, we probe the requirements for Sml1 degradation and identify several sites required for in vivo phosphorylation and degradation of Sml1 in response to DNA damage. Further, in a strain containing a mutation in Rnr1, rnr1-W688G, mutation of these sites in Sml1 causes lethality. Degradation of Sml1 is dependent on the 26S proteasome. We also show that degradation of phosphorylated Sml1 is dependent on the E2 ubiquitin-conjugating enzyme, Rad6, the E3 ubiquitin ligase, Ubr2, and the E2/E3-interacting protein, Mub1, which form a complex previously only implicated in the ubiquitylation of Rpn4.
机译：面对遗传毒性应激，核糖核苷酸还原酶（RNR）的调节对于细胞存活和基因组完整性很重要。 Mec1 / Rad53 / Dun1 DNA损伤反应激酶级联反应表现出对RNR活性的多方面控制，包括RNR抑制剂Sml1的调控。 DNA损伤后，Sml1降解，导致RNR上调dNTP库。在这里，我们探讨了Sml1降解的要求，并确定了体内Sml1磷酸化和降解以响应DNA损伤所需的几个位点。此外，在含有Rnr1突变rnr1-W688G的菌株中，Sml1中这些位点的突变会导致致命性。 Sml1的降解取决于26S蛋白酶体。我们还表明，磷酸化Sml1的降解取决于E2泛素结合酶Rad6，E3泛素连接酶Ubr2和E2 / E3相互作用蛋白Mub1，它们形成了以前仅与Rpn4泛素化有关的复合物。

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