Activation of the S-Phase Checkpoint Inhibits Degradation of the F-Box Protein Dia2

Andrew C. Kile; Deanna M. Koepp

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Activation of the S-Phase Checkpoint Inhibits Degradation of the F-Box Protein Dia2

机译：S相检查点的激活抑制F-Box蛋白Dia2的降解

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A stable genome is critical to cell viability and proliferation. During DNA replication, the S-phase checkpoint pathway responds to replication stress. In budding yeast, the chromatin-bound F-box protein Dia2 is required to maintain genomic stability and may help replication complexes overcome sites of damaged DNA and natural fragile regions. SCF (Skp1/Cul1/F-box protein) complexes are modular ubiquitin ligases. We show here that Dia2 is itself targeted for ubiquitin-mediated proteolysis and that activation of the S-phase checkpoint pathway inhibits Dia2 protein degradation. S-phase checkpoint mutants fail to stabilize Dia2 in response to replication stress. Deletion of DIA2 from these checkpoint mutants exacerbates their sensitivity to hydroxyurea, suggesting that stabilization of Dia2 contributes to the replication stress response. Unlike the case for other F-box proteins, deletion of the F-box domain in Dia2 does not stabilize the protein. Rather, an N-terminal domain that is also required for nuclear localization is necessary for degradation. When a strong nuclear localization signal (NLS) is added to dia2 mutants lacking this domain, the Dia2 protein is both stable and nuclear. Together, our results suggest that Dia2 protein turnover does not involve an autocatalytic mechanism and that Dia2 proteolysis is inhibited by activation of the replication stress response.

机译：稳定的基因组对细胞活力和增殖至关重要。在DNA复制过程中，S期检查点途径会响应复制压力。在发芽酵母中，需要结合染色质的F-box蛋白Dia2来维持基因组稳定性，并可能帮助复制复合物克服受损DNA和天然脆弱区域的位置。 SCF（ S kp1 / C ul1 / F -box蛋白）复合物是模块化泛素连接酶。我们在这里显示Dia2本身是针对泛素介导的蛋白水解作用的，而S期检查点途径的激活抑制了Dia2蛋白的降解。 S期检查点突变体未能稳定Dia2响应复制压力。从这些检查点突变体中删除 DIA2 会加剧其对羟基脲的敏感性，这表明Dia2的稳定有助于复制应激反应。与其他F-box蛋白的情况不同，Dia2中F-box结构域的缺失不能稳定该蛋白。而是，核定位所必需的N-末端结构域对于降解是必需的。当强核定位信号（NLS）添加到缺少该域的 dia2 突变体时，Dia2蛋白既稳定又有核。在一起，我们的结果表明，Dia2蛋白质更新不涉及自催化机制，并且Dia2蛋白水解被复制应激反应的激活所抑制。 展开▼

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《Molecular and Cellular Biology》 |2010年第1期|共12页

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Andrew C. Kile; Deanna M. Koepp;
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中图分类细胞生物学;

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1. Activation of the S-Phase Checkpoint Inhibits Degradation of the F-Box Protein Dia2 [J] . Andrew C. Kile, Deanna M. Koepp Molecular and Cellular Biology . 2010,第1期

机译：S相检查点的激活抑制F-Box蛋白Dia2的降解

2. The Saccharomyces cerevisiae F-Box Protein Dia2 Is a Mediator of S-Phase Checkpoint Recovery from DNA Damage [J] . Fong Chi Meng, Arumugam Ashwini, Koepp Deanna M. Genetics: A Periodical Record of Investigations Bearing on Heredity and Variation . 2013,第2期

机译：酿酒酵母F-Box蛋白Dia2是DNA损伤中S期检查点恢复的介体。

3. The Saccharomyces cerevisiae F-Box Protein Dia2 Is a Mediator of S-Phase Checkpoint Recovery from DNA Damage [J] . Ashwini Arumugam, Chi Meng Fong, Deanna M. Koepp Genetics: A Periodical Record of Investigations Bearing on Heredity and Variation . 2013,第2期

机译：酿酒酵母F-Box蛋白Dia2是DNA损伤中S期检查点恢复的介体。

4. Degraded collagen fragments activate NF-kB and protect human smooth muscle cells against apoptosis through induction of inhibitor of apoptosis proteins (lAPs) [C] . K. von Wnuck Lipinski, N. Ferri, B. Levka Nordrhein-Westfa?lische Akademie der Wissenschaften . 2005

机译：降解的胶原片段激活NF-KB并通过诱导凋亡蛋白抑制剂（圈）保护人平滑肌细胞免受细胞凋亡

5. Reverse Genetic Analysis of Arabidopsis F-Box Proteins: Role of Auxin-up-Regulated F-Box (AUF) 1 and 2 in Auxin Transport and Cytokinin Signaling. [D] . Zheng, Xiaohua. 2010

机译：拟南芥F-Box蛋白的反向遗传分析：生长素上调的F-Box（AUF）1和2在生长素转运和细胞分裂素信号传导中的作用。

6. Activation of the S-Phase Checkpoint Inhibits Degradation of the F-Box Protein Dia2 [O] . Andrew C. Kile, Deanna M. Koepp 2010

机译：S相检查点的激活抑制F-Box蛋白Dia2的降解

7. Activation of the S-Phase Checkpoint Inhibits Degradation of the F-Box Protein Dia2 ▿ [O] . Kile, Andrew C., Koepp, Deanna M. 2009

机译：S期检查站的激活抑制F-Box蛋白Dia2的降解

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2. 组合T细胞激活和/或检查点抑制剂治疗癌症的肽和肽模拟物 [P] . 中国专利： CN108473534A . 2018-08-31

3. DENATURATION/DEGRADATION INHIBITOR FOR INHIBITING DENATURATION AND/OR DEGRADATION OF PROTEIN DUE TO RADICAL, DENATURATION/DEGRADATION INHIBITOR-CONTAINING COMPOSITION INCLUDING THE SAME, AND METHOD FOR INHIBITING DENATURATION AND/OR DEGRADATION OF PROTEIN DUE TO RADICAL USING THE SAME [P] . 外国专利： JP2013170172A . 2013-09-02

机译：用于抑制蛋白质由于自由基而引起的变性和/或降解的变性/降解抑制剂，包括包含该成分的自由基的变性/降解抑制剂，以及由于自由基抑制蛋白质的变性和/或降解的方法

4. F-BOX PROTEINS OF UBIQUITIN LIGASE SCF COMPLEX THAT UBIQUITINATES AND DEGRADES CYCLIN E [P] . 外国专利： JP2001224380A . 2001-08-21

机译：泛素连接酶SCF复合物的F-box蛋白

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机译：使用选自以下的化合物：蛋白酶体抑制剂，自噬抑制剂，溶酶体抑制剂，高尔基体蛋白转运抑制剂，hsp90伴侣蛋白抑制剂，热休克反应激活剂，α和组蛋白脱乙酰酶抑制剂，使用11 -顺式-视黄醛或9-顺式-视黄醛以及选自蛋白酶体抑制剂，自噬抑制剂，核糖体抑制剂，高尔基体蛋白er，hsp90伴侣蛋白抑制剂，热休克反应激活剂，糖苷酶的化合物抑制剂和组蛋白脱乙酰基酶抑制剂，一种增加细胞中蛋白质的生化功能构象量的方法，用于治疗眼pcd的组合物药物，用于治疗色素性视网膜炎的药物组合物，用于治疗视网膜色素变性的试剂盒眼用pcd，用于治疗色素性视网膜炎的试剂盒，用于鉴定可用于治疗具有眼用pcd的个体的化合物的方法，

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Activation of the S-Phase Checkpoint Inhibits Degradation of the F-Box Protein Dia2

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