Human hRad1 but not hRad9 protects hHus1 from ubiquitin-proteasomal degradation.
Human hRad1 but not hRad9 protects hHus1 from ubiquitin-proteasomal degradation.
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人类 hRad1（而非 hRad9）可以保护 hHus1 免受泛素蛋白酶体降解。
DOI：
10.1038/sj.onc.1207658
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发表时间：
2004
期刊：
影响因子：
8
通讯作者：
Wang,Hong-Gang
中科院分区：
文献类型：
--
作者：
Hirai,Itaru;Sasaki,Terukatsu;Wang,Hong-Gang
三个Rad家族蛋白，Rad 9，Rad 1和Hus 1，可以相互作用并形成异源三聚体复合物，被认为在DNA完整性检查点途径的传感步骤中发挥作用，但Rad 9-Rad 1-Hus 1复合物组装的性质仍然是个谜。在这里，我们证明了人hRad 1蛋白在hRad 9-hRad 1-hHus 1异源三聚体复合物形成过程中起着重要的分子伴侣作用。与hRad 1相反，hHus 1是一种不稳定的蛋白质，通过泛素-蛋白酶体途径被主动降解。我们发现，用蛋白酶体特异性抑制剂处理细胞可以稳定hHus 1的表达。此外，hRad 1可以在hRad 9缺失的情况下与hHus 1结合，并保护hHus 1免受细胞质中的泛素化和降解。重要的是，遗传毒性应激诱导hRad 1表达并稳定hHus 1蛋白。综上所述，这些发现表明hRad 1作为潜在的内在伴侣在hHus 1稳定hRad 9-hRad 1-hHus 1检查点复合物形成中的新作用。
Three of the Rad family proteins, Rad9, Rad1, and Hus1, can interact with each other and form a heterotrimeric complex that is thought to play a role in the sensing step of the DNA integrity checkpoint pathways, but the nature of the Rad9–Rad1–Hus1 complex assembly remains enigmatic. Here, we demonstrate that the human hRad1 protein plays a significant role as molecular chaperone in the process of the hRad9–hRad1–hHus1 heterotrimeric complex formation. In contrast to hRad1, hHus1 is an unstable protein that is actively degraded via the ubiquitin–proteasome pathway. We show that treating cells with proteasome-specific inhibitors stabilizes hHus1 expression. Moreover, hRad1 can associate with hHus1 in the absence of hRad9 and protect hHus1 from ubiquitination and degradation in the cytoplasm. Importantly, genotoxic stress induces hRad1 expression and stabilizes the hHus1 protein. Taken together, these findings suggest a novel role of hRad1 as a potential intrinsic chaperone in the stabilization of hHus1 for the hRad9–hRad1–hHus1 checkpoint complex formation.